It is always judicious to avoid discussing religious or political issues because inevitably someone will be offended. As a lifetime member of the American Psychiatric Association, I adhere to its "Goldwater Rule," which proscribes the gratuitous diagnosis of any president absent of a formal face-to-face psychiatric evaluation. But it is perfectly permissible to express a psychiatric opinion about the contemporary national political scene.

Frankly, the status of the political arena has become ugly. This should not be surprising, given that at its core, politics is an unquenchable thirst for power, and Machiavelli is its anointed godfather. The current political zeitgeist of the country is becoming downright grotesque and spiteful. Although fierce political rivalry is widely accepted as a tradition to achieve the national goals promulgated by each party, what we are witnessing today is a veritable blood sport fueled by “hyper-partisanship,” where drawing blood, not promoting the public good, has become an undisguised intent.

The intensity of hyper-partisanship has engulfed the collective national psyche and is bordering on the “religification” of politics. What used to be reasonable political views have been transformed into irrefutable articles of faith that do not lend themselves to rational debate or productive compromise. The metastasis of social media into our daily lives over the past decade is catalyzing the venomous crossfire across the political divide that used to be passionate and civil, but recently has degenerated into a raucous cacophony of hateful speech. Thoughtful debate of issues that promote the public good is becoming scarce. Instead of effectively defending the validity of their arguments, extremists focus on spewing accusations and ad hominem insults. It is worrisome that both fringe groups tenaciously uphold fixed and extreme political positions, the tenets of which can never be challenged.

Psychiatrically, those extreme ideological positions appear to be consistent with Jasper’s criteria for a delusion (a belief with an unparalleled degree of subjective feeling of certainty that cannot be influenced by experience or arguments) or McHugh’s definition of an overvalued idea, which resembles an egosyntonic obsession that is relished, amplified, and defended. Given that extremism is not just a “folie à deux” shared by 2 individuals but by many individuals, it may qualify as a “folie en masse.”
 

Having a political orientation is perfectly normal, a healthy evidence of absence of indolent apathy. However, the unconstrained fervor of political extremism can be as psychologically unhealthy as lethargic passivity. A significant segment of the population may see some merit on both sides of the gaping political chasm, but they are appalled by the intransigence of political extremism, which has become an impediment to the constructive compromise that is vital for progress in politics and in all human interactions.

Beliefs are a transcendent human trait. Homo sapiens represent the only animal species endowed by evolution with a large prefrontal cortex that enables each of its members to harbor a belief system. It prompts me to propose that Descartes’ famous dictum “I think, therefore I am” be revised to “I believe, therefore I am human.” But while many beliefs are reasonable and anchored in reality, irrational beliefs are odd and ambiguous, ranging from superstitions and overvalued ideas to conspiracy theories and cults, which I wrote about a decade ago.¹ In fact, epidemiologic research studies have confirmed a high prevalence of subthreshold and pre-psychotic beliefs in the general population.^2-5 Thus, radical political partisanship falls on the extreme end of that continuum.

The zeitgeist generated by extreme partisanship is intellectually stunting and emotionally numbing. Psychiatrists may wonder what consequences the intense anger and antipathy and scarcity of compromise between the opposing parties will have for the country’s citizens. Although psychiatrists cannot repair the dysfunctional political fragmentation at the national level, we can help patients who may be negatively affected by the conflicts permeating the national scene when we read or watch the daily news.

Just as it is disturbing for children to watch their parents undermine each other by arguing ferociously and hurling insults, so it is for a populace aghast at how frenzied and intolerant their leaders and their extremist followers have become, failing to work together for the common good and adversely impacting the mental health zeitgeist.

It is always judicious to avoid discussing religious or political issues because inevitably someone will be offended. As a lifetime member of the American Psychiatric Association, I adhere to its "Goldwater Rule," which proscribes the gratuitous diagnosis of any president absent of a formal face-to-face psychiatric evaluation. But it is perfectly permissible to express a psychiatric opinion about the contemporary national political scene.

Frankly, the status of the political arena has become ugly. This should not be surprising, given that at its core, politics is an unquenchable thirst for power, and Machiavelli is its anointed godfather. The current political zeitgeist of the country is becoming downright grotesque and spiteful. Although fierce political rivalry is widely accepted as a tradition to achieve the national goals promulgated by each party, what we are witnessing today is a veritable blood sport fueled by “hyper-partisanship,” where drawing blood, not promoting the public good, has become an undisguised intent.

The intensity of hyper-partisanship has engulfed the collective national psyche and is bordering on the “religification” of politics. What used to be reasonable political views have been transformed into irrefutable articles of faith that do not lend themselves to rational debate or productive compromise. The metastasis of social media into our daily lives over the past decade is catalyzing the venomous crossfire across the political divide that used to be passionate and civil, but recently has degenerated into a raucous cacophony of hateful speech. Thoughtful debate of issues that promote the public good is becoming scarce. Instead of effectively defending the validity of their arguments, extremists focus on spewing accusations and ad hominem insults. It is worrisome that both fringe groups tenaciously uphold fixed and extreme political positions, the tenets of which can never be challenged.

Psychiatrically, those extreme ideological positions appear to be consistent with Jasper’s criteria for a delusion (a belief with an unparalleled degree of subjective feeling of certainty that cannot be influenced by experience or arguments) or McHugh’s definition of an overvalued idea, which resembles an egosyntonic obsession that is relished, amplified, and defended. Given that extremism is not just a “folie à deux” shared by 2 individuals but by many individuals, it may qualify as a “folie en masse.”
 

Having a political orientation is perfectly normal, a healthy evidence of absence of indolent apathy. However, the unconstrained fervor of political extremism can be as psychologically unhealthy as lethargic passivity. A significant segment of the population may see some merit on both sides of the gaping political chasm, but they are appalled by the intransigence of political extremism, which has become an impediment to the constructive compromise that is vital for progress in politics and in all human interactions.

Beliefs are a transcendent human trait. Homo sapiens represent the only animal species endowed by evolution with a large prefrontal cortex that enables each of its members to harbor a belief system. It prompts me to propose that Descartes’ famous dictum “I think, therefore I am” be revised to “I believe, therefore I am human.” But while many beliefs are reasonable and anchored in reality, irrational beliefs are odd and ambiguous, ranging from superstitions and overvalued ideas to conspiracy theories and cults, which I wrote about a decade ago.¹ In fact, epidemiologic research studies have confirmed a high prevalence of subthreshold and pre-psychotic beliefs in the general population.^2-5 Thus, radical political partisanship falls on the extreme end of that continuum.

The zeitgeist generated by extreme partisanship is intellectually stunting and emotionally numbing. Psychiatrists may wonder what consequences the intense anger and antipathy and scarcity of compromise between the opposing parties will have for the country’s citizens. Although psychiatrists cannot repair the dysfunctional political fragmentation at the national level, we can help patients who may be negatively affected by the conflicts permeating the national scene when we read or watch the daily news.

Just as it is disturbing for children to watch their parents undermine each other by arguing ferociously and hurling insults, so it is for a populace aghast at how frenzied and intolerant their leaders and their extremist followers have become, failing to work together for the common good and adversely impacting the mental health zeitgeist.

It is always judicious to avoid discussing religious or political issues because inevitably someone will be offended. As a lifetime member of the American Psychiatric Association, I adhere to its "Goldwater Rule," which proscribes the gratuitous diagnosis of any president absent of a formal face-to-face psychiatric evaluation. But it is perfectly permissible to express a psychiatric opinion about the contemporary national political scene.

Frankly, the status of the political arena has become ugly. This should not be surprising, given that at its core, politics is an unquenchable thirst for power, and Machiavelli is its anointed godfather. The current political zeitgeist of the country is becoming downright grotesque and spiteful. Although fierce political rivalry is widely accepted as a tradition to achieve the national goals promulgated by each party, what we are witnessing today is a veritable blood sport fueled by “hyper-partisanship,” where drawing blood, not promoting the public good, has become an undisguised intent.

The intensity of hyper-partisanship has engulfed the collective national psyche and is bordering on the “religification” of politics. What used to be reasonable political views have been transformed into irrefutable articles of faith that do not lend themselves to rational debate or productive compromise. The metastasis of social media into our daily lives over the past decade is catalyzing the venomous crossfire across the political divide that used to be passionate and civil, but recently has degenerated into a raucous cacophony of hateful speech. Thoughtful debate of issues that promote the public good is becoming scarce. Instead of effectively defending the validity of their arguments, extremists focus on spewing accusations and ad hominem insults. It is worrisome that both fringe groups tenaciously uphold fixed and extreme political positions, the tenets of which can never be challenged.

Psychiatrically, those extreme ideological positions appear to be consistent with Jasper’s criteria for a delusion (a belief with an unparalleled degree of subjective feeling of certainty that cannot be influenced by experience or arguments) or McHugh’s definition of an overvalued idea, which resembles an egosyntonic obsession that is relished, amplified, and defended. Given that extremism is not just a “folie à deux” shared by 2 individuals but by many individuals, it may qualify as a “folie en masse.”
 

Having a political orientation is perfectly normal, a healthy evidence of absence of indolent apathy. However, the unconstrained fervor of political extremism can be as psychologically unhealthy as lethargic passivity. A significant segment of the population may see some merit on both sides of the gaping political chasm, but they are appalled by the intransigence of political extremism, which has become an impediment to the constructive compromise that is vital for progress in politics and in all human interactions.

Beliefs are a transcendent human trait. Homo sapiens represent the only animal species endowed by evolution with a large prefrontal cortex that enables each of its members to harbor a belief system. It prompts me to propose that Descartes’ famous dictum “I think, therefore I am” be revised to “I believe, therefore I am human.” But while many beliefs are reasonable and anchored in reality, irrational beliefs are odd and ambiguous, ranging from superstitions and overvalued ideas to conspiracy theories and cults, which I wrote about a decade ago.¹ In fact, epidemiologic research studies have confirmed a high prevalence of subthreshold and pre-psychotic beliefs in the general population.^2-5 Thus, radical political partisanship falls on the extreme end of that continuum.

The zeitgeist generated by extreme partisanship is intellectually stunting and emotionally numbing. Psychiatrists may wonder what consequences the intense anger and antipathy and scarcity of compromise between the opposing parties will have for the country’s citizens. Although psychiatrists cannot repair the dysfunctional political fragmentation at the national level, we can help patients who may be negatively affected by the conflicts permeating the national scene when we read or watch the daily news.

Just as it is disturbing for children to watch their parents undermine each other by arguing ferociously and hurling insults, so it is for a populace aghast at how frenzied and intolerant their leaders and their extremist followers have become, failing to work together for the common good and adversely impacting the mental health zeitgeist.

CASE Medication management

Mr. L, age 58, presents to the outpatient psychiatric clinic seeking treatment for attention-deficit/hyperactivity disorder (ADHD), which was first diagnosed 11 years ago. Since discontinuing his ADHD medication, lisdexamfetamine 60 mg/d, 8 months ago, he has not been completing tasks and has been distracted in his job as a limousine driver. Mr. L says that when he was taking the medication, “I could focus and prioritize.” He reports that he has trouble retaining information and is easily distracted. He says he generally is organized with appointments and keeping track of things but is messy, forgetful, tardy, and impatient. Procrastination is an ongoing problem. He denies misplacing things or being impulsive. Mr. L reports that as a child he was frequently reprimanded for talking in class. He states, “I get in trouble even now for talking too much.”

Mr. L is cooperative and polite, maintains good eye contact, and is alert. No psychomotor abnormalities are noted. His speech is spontaneous and coherent, with normal rate, rhythm, and volume. He reports that his mood is “all right,” and denies suicidal or homicidal ideation. His insight is full, judgment is intact, and thought is linear and logical. Mr. L sleeps 5 hours at night and takes a nap during the day, but his energy varies.

His psychiatric history is negative for suicide attempts or hospitalizations. Mr. L denies a history of major depressive episodes, manic symptoms, hallucinations, or delusions. Anxiety history is negative for excessive worrying, obsessions and compulsions, and panic attacks. Mr. L has no family history of mental illness or substance abuse, and he denies any personal history of drug use. He stopped using tobacco 14 years ago. Mr. L says he drinks 3 caffeinated drinks a day and 2 glasses of wine once a week. Previous medications included lisdexamfetamine, dextroamphetamine/amphetamine, and bupropion. His medical history is notable for irritable bowel syndrome, gastroesophageal reflux disease, hyperlipidemia, hemorrhoids, recently treated H. pylori, eczema, and benign prostatic hyperplasia. He has no history of head trauma. He is currently taking omeprazole EC, 20 mg twice a day, tamsulosin, 0.4 mg at bedtime, aspirin, 81 mg/d, and cimetidine, 150 mg twice a day.

A review of systems is negative. Vital signs are unremarkable. A recent electrocardiogram (EKG) showed normal sinus rhythm. Thyroid-stimulating hormone, comprehensive metabolic panel (CMP), lipids, iron, vitamin B₁₂, folate, complete blood count (CBC), hemoglobin A_1c, and urine analysis are normal, except for mildly elevated low-density lipoprotein. Testing for hepatitis C is negative.

The previous diagnosis of ADHD is confirmed, and Mr. L is started on methylphenidate extended-release (ER), 27 mg every morning. At 1-month follow-up, Mr. L demonstrates good tolerance to the medication, and reports that he feels the dose is appropriate; no changes are made. The following month, Mr. L reports that, although the medication still works well, he feels anxious, irritable, and agitated, and has palpitations. He reports feeling tired during the day, with a return of energy at night, resulting in difficulty sleeping. He also is experiencing nausea and headaches, and has lost 15 lb. Mr. L thinks that the symptoms, particularly the weight loss, are adverse effects from the methylphenidate ER and requests a lower dose. The methylphenidate ER dose is decreased to 18 mg/d.

[polldaddy:9928295]

The author’s observations

Anxiety, irritability, agitation, and palpitations can all be symptoms of stimulant medications.^1,2 There are numerous other iatrogenic causes, including steroid-based asthma treatments, thyroid medications, antidepressants in bipolar patients, and caffeine-based migraine treatments. Mr. L’s theory that his 15-lb weight loss was the result of his methylphenidate ER dose being too high was a reasonable one. Often, medication doses need to be adjusted with weight changes. His decrease in energy during the day could be explained by the methylphenidate ER controlling his hyperactive symptoms, which include high energy. At night, when the medication wears off, his hyperactivity symptoms could be returning, which would account for the increase in energy when he gets home from work. Although longer-acting stimulants tend to have a more benign adverse effects profile, they can cause insomnia if they are still in the patient’s system at bedtime. Shorter-acting stimulants wear off quickly but can be advantageous for patients who want to target concentration during certain times of day, such as for school and homework.

TREATMENT A surprising cause

The next month, Mr. L presents to the emergency room complaining of jitteriness, headache, and tingling in his fingers, and is evaluated for suspected carbon monoxide (CO) poisoning. Three months earlier, he had noted the odor of exhaust fumes in the limousine he drives 7 days a week. He took it to the mechanic twice for evaluation, but no cause was found. Despite his concerns, he continued to drive the car until an older client, in frail health, suddenly became short of breath and developed chest pain shortly after entering his vehicle, on a day when the odor was particularly bad. Before that, a family of passengers had complained of headaches upon entering his vehicle. The third time he brought his car to be checked, the mechanic identified an exhaust system leak.

[polldaddy:9928298]

The author’s observations

Work-up for suspected CO poisoning includes ABG, COHb level, CBC, basic metabolic panel, EKG, cardiac enzymes, and chest radiography, as well as other laboratory tests as deemed appropriate. Treatment includes oxygen by mask for low-level poisoning.

High levels of poisoning may require hyperbaric oxygen, which should be considered for patients who are unconscious or have an abnormal score on the Carbon Monoxide Neuropsychological Screening Battery, COHb of >40%, signs of cardiac ischemia or arrhythmia, history of ischemic heart disease with COHb level >20%, recurrent symptoms for up to 3 weeks, or symptoms that have not resolved with normobaric oxygen after 4 to 6 hours.⁹ Any pregnant woman with CO poisoning should receive hyperbaric therapy.¹⁰

OUTCOME Lasting improvement

Mr. L presents for follow-up in the psychiatric clinic 3 weeks after his emergency room visit. After his limousine was repaired, his symptoms resolved. He no longer experiences fatigue during the day with higher energy at night, palpitations, jitteriness, headache, or tingling. His concentration has improved, so he opts to stick with the 18-mg dose of methylphenidate ER rather than increase it to the initial dose. He places a CO detector in his vehicle, which proves to be a good decision when it gives him a warning that the exhaust leak had not been properly repaired.

[polldaddy:9928299]

The author’s observations

Although the correct cause of Mr. L’s symptoms was found incidentally, this case is an important reminder to always consider medical causes in the differential diagnosis. We are taught in medical school to look first for horses (more likely causes), not zebras (less likely causes), but sometimes zebras do occur. Be mindful that medical causes should be considered not only for symptoms of primary illnesses, but also for symptoms thought to be caused by adverse effects of medications. The differential diagnosis for Mr. L’s symptoms (palpitations, agitation, anxiety, irritability, weight loss, fatigue, nausea, and headache) included metabolic and endocrine abnormalities (thyroid disease, pheochromocytoma, hypoglycemia); psychiatric conditions (panic, bipolar disorder, depression); substance abuse (caffeine, cocaine, amphetamines); immune disorders; cardiac disorders; malignancy; toxic exposure; infectious sources; and nutritional deficiencies. CO poisoning can cause many of these symptoms (Table 2).^1,2,8

Intentional CO poisoning should be considered in an obtunded or unconscious patient with depression. Patients may consider CO poisoning a more peaceful way to complete suicide than shooting, cutting, or hanging. As for unintentional poisoning, clinical suspicion can be increased by time of year, occupation, locale, and smoking status. Winter months increase risk because of the high use of heating devices, cars warming up in the garage, closed fireplace flues, and vehicle tailpipes blocked by snow. As in Mr. L’s case, occupation also may increase suspicion; drivers, mechanics, tollbooth operators, parking attendants, miners, and firefighters are all at increased risk for CO poisoning. Regarding locale, polluted urban environments as well as cold climates requiring heating sources cause higher risks for CO exposure. Rarely, excessive smoking can result in CO poisoning. The author once had a patient with schizophrenia who was admitted to the hospital with delirium. It was determined that he had CO poisoning from his 5-pack-a-day smoking habit.

Psychiatric patients often have the frustrating experience of their physical symptoms being attributed to psychiatric causes, which results in major medical issues being overlooked. We psychiatrists can fall into the same trap of overlooking medical illnesses, as indicated in this case, where Mr. L’s CO poisoning initially was attributed to adverse effects of his psychiatric medication.

CASE Medication management

Mr. L, age 58, presents to the outpatient psychiatric clinic seeking treatment for attention-deficit/hyperactivity disorder (ADHD), which was first diagnosed 11 years ago. Since discontinuing his ADHD medication, lisdexamfetamine 60 mg/d, 8 months ago, he has not been completing tasks and has been distracted in his job as a limousine driver. Mr. L says that when he was taking the medication, “I could focus and prioritize.” He reports that he has trouble retaining information and is easily distracted. He says he generally is organized with appointments and keeping track of things but is messy, forgetful, tardy, and impatient. Procrastination is an ongoing problem. He denies misplacing things or being impulsive. Mr. L reports that as a child he was frequently reprimanded for talking in class. He states, “I get in trouble even now for talking too much.”

Mr. L is cooperative and polite, maintains good eye contact, and is alert. No psychomotor abnormalities are noted. His speech is spontaneous and coherent, with normal rate, rhythm, and volume. He reports that his mood is “all right,” and denies suicidal or homicidal ideation. His insight is full, judgment is intact, and thought is linear and logical. Mr. L sleeps 5 hours at night and takes a nap during the day, but his energy varies.

His psychiatric history is negative for suicide attempts or hospitalizations. Mr. L denies a history of major depressive episodes, manic symptoms, hallucinations, or delusions. Anxiety history is negative for excessive worrying, obsessions and compulsions, and panic attacks. Mr. L has no family history of mental illness or substance abuse, and he denies any personal history of drug use. He stopped using tobacco 14 years ago. Mr. L says he drinks 3 caffeinated drinks a day and 2 glasses of wine once a week. Previous medications included lisdexamfetamine, dextroamphetamine/amphetamine, and bupropion. His medical history is notable for irritable bowel syndrome, gastroesophageal reflux disease, hyperlipidemia, hemorrhoids, recently treated H. pylori, eczema, and benign prostatic hyperplasia. He has no history of head trauma. He is currently taking omeprazole EC, 20 mg twice a day, tamsulosin, 0.4 mg at bedtime, aspirin, 81 mg/d, and cimetidine, 150 mg twice a day.

A review of systems is negative. Vital signs are unremarkable. A recent electrocardiogram (EKG) showed normal sinus rhythm. Thyroid-stimulating hormone, comprehensive metabolic panel (CMP), lipids, iron, vitamin B₁₂, folate, complete blood count (CBC), hemoglobin A_1c, and urine analysis are normal, except for mildly elevated low-density lipoprotein. Testing for hepatitis C is negative.

The previous diagnosis of ADHD is confirmed, and Mr. L is started on methylphenidate extended-release (ER), 27 mg every morning. At 1-month follow-up, Mr. L demonstrates good tolerance to the medication, and reports that he feels the dose is appropriate; no changes are made. The following month, Mr. L reports that, although the medication still works well, he feels anxious, irritable, and agitated, and has palpitations. He reports feeling tired during the day, with a return of energy at night, resulting in difficulty sleeping. He also is experiencing nausea and headaches, and has lost 15 lb. Mr. L thinks that the symptoms, particularly the weight loss, are adverse effects from the methylphenidate ER and requests a lower dose. The methylphenidate ER dose is decreased to 18 mg/d.

[polldaddy:9928295]

The author’s observations

Anxiety, irritability, agitation, and palpitations can all be symptoms of stimulant medications.^1,2 There are numerous other iatrogenic causes, including steroid-based asthma treatments, thyroid medications, antidepressants in bipolar patients, and caffeine-based migraine treatments. Mr. L’s theory that his 15-lb weight loss was the result of his methylphenidate ER dose being too high was a reasonable one. Often, medication doses need to be adjusted with weight changes. His decrease in energy during the day could be explained by the methylphenidate ER controlling his hyperactive symptoms, which include high energy. At night, when the medication wears off, his hyperactivity symptoms could be returning, which would account for the increase in energy when he gets home from work. Although longer-acting stimulants tend to have a more benign adverse effects profile, they can cause insomnia if they are still in the patient’s system at bedtime. Shorter-acting stimulants wear off quickly but can be advantageous for patients who want to target concentration during certain times of day, such as for school and homework.

TREATMENT A surprising cause

The next month, Mr. L presents to the emergency room complaining of jitteriness, headache, and tingling in his fingers, and is evaluated for suspected carbon monoxide (CO) poisoning. Three months earlier, he had noted the odor of exhaust fumes in the limousine he drives 7 days a week. He took it to the mechanic twice for evaluation, but no cause was found. Despite his concerns, he continued to drive the car until an older client, in frail health, suddenly became short of breath and developed chest pain shortly after entering his vehicle, on a day when the odor was particularly bad. Before that, a family of passengers had complained of headaches upon entering his vehicle. The third time he brought his car to be checked, the mechanic identified an exhaust system leak.

[polldaddy:9928298]

The author’s observations

Work-up for suspected CO poisoning includes ABG, COHb level, CBC, basic metabolic panel, EKG, cardiac enzymes, and chest radiography, as well as other laboratory tests as deemed appropriate. Treatment includes oxygen by mask for low-level poisoning.

High levels of poisoning may require hyperbaric oxygen, which should be considered for patients who are unconscious or have an abnormal score on the Carbon Monoxide Neuropsychological Screening Battery, COHb of >40%, signs of cardiac ischemia or arrhythmia, history of ischemic heart disease with COHb level >20%, recurrent symptoms for up to 3 weeks, or symptoms that have not resolved with normobaric oxygen after 4 to 6 hours.⁹ Any pregnant woman with CO poisoning should receive hyperbaric therapy.¹⁰

OUTCOME Lasting improvement

Mr. L presents for follow-up in the psychiatric clinic 3 weeks after his emergency room visit. After his limousine was repaired, his symptoms resolved. He no longer experiences fatigue during the day with higher energy at night, palpitations, jitteriness, headache, or tingling. His concentration has improved, so he opts to stick with the 18-mg dose of methylphenidate ER rather than increase it to the initial dose. He places a CO detector in his vehicle, which proves to be a good decision when it gives him a warning that the exhaust leak had not been properly repaired.

[polldaddy:9928299]

The author’s observations

Although the correct cause of Mr. L’s symptoms was found incidentally, this case is an important reminder to always consider medical causes in the differential diagnosis. We are taught in medical school to look first for horses (more likely causes), not zebras (less likely causes), but sometimes zebras do occur. Be mindful that medical causes should be considered not only for symptoms of primary illnesses, but also for symptoms thought to be caused by adverse effects of medications. The differential diagnosis for Mr. L’s symptoms (palpitations, agitation, anxiety, irritability, weight loss, fatigue, nausea, and headache) included metabolic and endocrine abnormalities (thyroid disease, pheochromocytoma, hypoglycemia); psychiatric conditions (panic, bipolar disorder, depression); substance abuse (caffeine, cocaine, amphetamines); immune disorders; cardiac disorders; malignancy; toxic exposure; infectious sources; and nutritional deficiencies. CO poisoning can cause many of these symptoms (Table 2).^1,2,8

Intentional CO poisoning should be considered in an obtunded or unconscious patient with depression. Patients may consider CO poisoning a more peaceful way to complete suicide than shooting, cutting, or hanging. As for unintentional poisoning, clinical suspicion can be increased by time of year, occupation, locale, and smoking status. Winter months increase risk because of the high use of heating devices, cars warming up in the garage, closed fireplace flues, and vehicle tailpipes blocked by snow. As in Mr. L’s case, occupation also may increase suspicion; drivers, mechanics, tollbooth operators, parking attendants, miners, and firefighters are all at increased risk for CO poisoning. Regarding locale, polluted urban environments as well as cold climates requiring heating sources cause higher risks for CO exposure. Rarely, excessive smoking can result in CO poisoning. The author once had a patient with schizophrenia who was admitted to the hospital with delirium. It was determined that he had CO poisoning from his 5-pack-a-day smoking habit.

Psychiatric patients often have the frustrating experience of their physical symptoms being attributed to psychiatric causes, which results in major medical issues being overlooked. We psychiatrists can fall into the same trap of overlooking medical illnesses, as indicated in this case, where Mr. L’s CO poisoning initially was attributed to adverse effects of his psychiatric medication.

CASE Medication management

Mr. L, age 58, presents to the outpatient psychiatric clinic seeking treatment for attention-deficit/hyperactivity disorder (ADHD), which was first diagnosed 11 years ago. Since discontinuing his ADHD medication, lisdexamfetamine 60 mg/d, 8 months ago, he has not been completing tasks and has been distracted in his job as a limousine driver. Mr. L says that when he was taking the medication, “I could focus and prioritize.” He reports that he has trouble retaining information and is easily distracted. He says he generally is organized with appointments and keeping track of things but is messy, forgetful, tardy, and impatient. Procrastination is an ongoing problem. He denies misplacing things or being impulsive. Mr. L reports that as a child he was frequently reprimanded for talking in class. He states, “I get in trouble even now for talking too much.”

Mr. L is cooperative and polite, maintains good eye contact, and is alert. No psychomotor abnormalities are noted. His speech is spontaneous and coherent, with normal rate, rhythm, and volume. He reports that his mood is “all right,” and denies suicidal or homicidal ideation. His insight is full, judgment is intact, and thought is linear and logical. Mr. L sleeps 5 hours at night and takes a nap during the day, but his energy varies.

His psychiatric history is negative for suicide attempts or hospitalizations. Mr. L denies a history of major depressive episodes, manic symptoms, hallucinations, or delusions. Anxiety history is negative for excessive worrying, obsessions and compulsions, and panic attacks. Mr. L has no family history of mental illness or substance abuse, and he denies any personal history of drug use. He stopped using tobacco 14 years ago. Mr. L says he drinks 3 caffeinated drinks a day and 2 glasses of wine once a week. Previous medications included lisdexamfetamine, dextroamphetamine/amphetamine, and bupropion. His medical history is notable for irritable bowel syndrome, gastroesophageal reflux disease, hyperlipidemia, hemorrhoids, recently treated H. pylori, eczema, and benign prostatic hyperplasia. He has no history of head trauma. He is currently taking omeprazole EC, 20 mg twice a day, tamsulosin, 0.4 mg at bedtime, aspirin, 81 mg/d, and cimetidine, 150 mg twice a day.

A review of systems is negative. Vital signs are unremarkable. A recent electrocardiogram (EKG) showed normal sinus rhythm. Thyroid-stimulating hormone, comprehensive metabolic panel (CMP), lipids, iron, vitamin B₁₂, folate, complete blood count (CBC), hemoglobin A_1c, and urine analysis are normal, except for mildly elevated low-density lipoprotein. Testing for hepatitis C is negative.

The previous diagnosis of ADHD is confirmed, and Mr. L is started on methylphenidate extended-release (ER), 27 mg every morning. At 1-month follow-up, Mr. L demonstrates good tolerance to the medication, and reports that he feels the dose is appropriate; no changes are made. The following month, Mr. L reports that, although the medication still works well, he feels anxious, irritable, and agitated, and has palpitations. He reports feeling tired during the day, with a return of energy at night, resulting in difficulty sleeping. He also is experiencing nausea and headaches, and has lost 15 lb. Mr. L thinks that the symptoms, particularly the weight loss, are adverse effects from the methylphenidate ER and requests a lower dose. The methylphenidate ER dose is decreased to 18 mg/d.

[polldaddy:9928295]

The author’s observations

Anxiety, irritability, agitation, and palpitations can all be symptoms of stimulant medications.^1,2 There are numerous other iatrogenic causes, including steroid-based asthma treatments, thyroid medications, antidepressants in bipolar patients, and caffeine-based migraine treatments. Mr. L’s theory that his 15-lb weight loss was the result of his methylphenidate ER dose being too high was a reasonable one. Often, medication doses need to be adjusted with weight changes. His decrease in energy during the day could be explained by the methylphenidate ER controlling his hyperactive symptoms, which include high energy. At night, when the medication wears off, his hyperactivity symptoms could be returning, which would account for the increase in energy when he gets home from work. Although longer-acting stimulants tend to have a more benign adverse effects profile, they can cause insomnia if they are still in the patient’s system at bedtime. Shorter-acting stimulants wear off quickly but can be advantageous for patients who want to target concentration during certain times of day, such as for school and homework.

TREATMENT A surprising cause

The next month, Mr. L presents to the emergency room complaining of jitteriness, headache, and tingling in his fingers, and is evaluated for suspected carbon monoxide (CO) poisoning. Three months earlier, he had noted the odor of exhaust fumes in the limousine he drives 7 days a week. He took it to the mechanic twice for evaluation, but no cause was found. Despite his concerns, he continued to drive the car until an older client, in frail health, suddenly became short of breath and developed chest pain shortly after entering his vehicle, on a day when the odor was particularly bad. Before that, a family of passengers had complained of headaches upon entering his vehicle. The third time he brought his car to be checked, the mechanic identified an exhaust system leak.

[polldaddy:9928298]

The author’s observations

Work-up for suspected CO poisoning includes ABG, COHb level, CBC, basic metabolic panel, EKG, cardiac enzymes, and chest radiography, as well as other laboratory tests as deemed appropriate. Treatment includes oxygen by mask for low-level poisoning.

High levels of poisoning may require hyperbaric oxygen, which should be considered for patients who are unconscious or have an abnormal score on the Carbon Monoxide Neuropsychological Screening Battery, COHb of >40%, signs of cardiac ischemia or arrhythmia, history of ischemic heart disease with COHb level >20%, recurrent symptoms for up to 3 weeks, or symptoms that have not resolved with normobaric oxygen after 4 to 6 hours.⁹ Any pregnant woman with CO poisoning should receive hyperbaric therapy.¹⁰

OUTCOME Lasting improvement

Mr. L presents for follow-up in the psychiatric clinic 3 weeks after his emergency room visit. After his limousine was repaired, his symptoms resolved. He no longer experiences fatigue during the day with higher energy at night, palpitations, jitteriness, headache, or tingling. His concentration has improved, so he opts to stick with the 18-mg dose of methylphenidate ER rather than increase it to the initial dose. He places a CO detector in his vehicle, which proves to be a good decision when it gives him a warning that the exhaust leak had not been properly repaired.

[polldaddy:9928299]

The author’s observations

Although the correct cause of Mr. L’s symptoms was found incidentally, this case is an important reminder to always consider medical causes in the differential diagnosis. We are taught in medical school to look first for horses (more likely causes), not zebras (less likely causes), but sometimes zebras do occur. Be mindful that medical causes should be considered not only for symptoms of primary illnesses, but also for symptoms thought to be caused by adverse effects of medications. The differential diagnosis for Mr. L’s symptoms (palpitations, agitation, anxiety, irritability, weight loss, fatigue, nausea, and headache) included metabolic and endocrine abnormalities (thyroid disease, pheochromocytoma, hypoglycemia); psychiatric conditions (panic, bipolar disorder, depression); substance abuse (caffeine, cocaine, amphetamines); immune disorders; cardiac disorders; malignancy; toxic exposure; infectious sources; and nutritional deficiencies. CO poisoning can cause many of these symptoms (Table 2).^1,2,8

Intentional CO poisoning should be considered in an obtunded or unconscious patient with depression. Patients may consider CO poisoning a more peaceful way to complete suicide than shooting, cutting, or hanging. As for unintentional poisoning, clinical suspicion can be increased by time of year, occupation, locale, and smoking status. Winter months increase risk because of the high use of heating devices, cars warming up in the garage, closed fireplace flues, and vehicle tailpipes blocked by snow. As in Mr. L’s case, occupation also may increase suspicion; drivers, mechanics, tollbooth operators, parking attendants, miners, and firefighters are all at increased risk for CO poisoning. Regarding locale, polluted urban environments as well as cold climates requiring heating sources cause higher risks for CO exposure. Rarely, excessive smoking can result in CO poisoning. The author once had a patient with schizophrenia who was admitted to the hospital with delirium. It was determined that he had CO poisoning from his 5-pack-a-day smoking habit.

Psychiatric patients often have the frustrating experience of their physical symptoms being attributed to psychiatric causes, which results in major medical issues being overlooked. We psychiatrists can fall into the same trap of overlooking medical illnesses, as indicated in this case, where Mr. L’s CO poisoning initially was attributed to adverse effects of his psychiatric medication.

Tobacco-related cardiovascular disease is the primary reason adults with schizophrenia die on average 28 years earlier than their peers in the U.S. general population.¹ To address this, clinicians need to prioritize smoking cessation and emphasize to patients with schizophrenia that quitting is the most important change they can make to improve their health. Here are 4 ways to help patients with schizophrenia quit smoking.

Provide hope, but be realistic. Most patients with schizophrenia who smoke want to quit; however, patients and clinicians alike have been discouraged by low quit rates and high relapse rates. Smoking often is viewed as one of the few remaining personal freedoms, as a lower priority than active psychiatric symptoms, or even as neuroprotective. By perpetuating these falsehoods and avoiding addressing smoking cessation, we are failing our patients.

With persistent engagement and use of effective pharmacotherapeutic interventions, smoking cessation is attainable and does not worsen psychiatric symptoms. Additionally, smoking cessation could save patients >$4,000 a year. It is crucial to make smoking cessation a priority at every appointment, and to offer patients hope and practical guidance through repeated attempts to quit.

Offer varenicline. For patients with schizophrenia, cessation counseling or behavioral interventions alone have a poor efficacy rate of approximately 5% (compared with 15% to 20% in the general population).² Varenicline is the most effective smoking cessation treatment; it increases cessation rates 5-fold among patients with schizophrenia.³ As demonstrated by the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES),⁴ varenicline does not lead to an increased risk of suicidality or serious neuropsychiatric adverse effects.

When starting a patient on varenicline, set a quit date 4 weeks from medication initiation. Individuals with schizophrenia often have a greater smoking burden and experience more intense symptoms of nicotine withdrawal. A 4-week period between medication initiation and the quit date will allow these patients to gradually experience reduced cravings and separate minor adverse effects of the medication from those of nicotine withdrawal. Concurrent prescription of nicotine replacement therapy (eg, patch, gum, lozenge, inhaler) also is safe and can assist in quit attempts.

Consider varenicline maintenance therapy. After a successful quit attempt, increase the likelihood of sustained cessation by continuing varenicline beyond 12 weeks. Varenicline can be used as a maintenance medication to prevent smoking relapse in patients with schizophrenia; when prescribed to these patients for an additional 3 months, it can reduce the relapse rate similarly to that seen in smokers in the general population.⁵

Adjust antipsychotic dosages. Tobacco smoke increases the activity of cytochrome P450 1A2, which metabolizes several antipsychotics. Thus, after successful smoking cessation, concentrations of clozapine, fluphenazine, haloperidol, and olanzapine may increase, and dose reduction may be warranted. Conversely, if a patient resumes smoking, dosages of these medications may need to be increased.

Acknowledgments

The authors thank Anne Eden Evins, MD, MPH, and Corinne Cather, PhD, for their input on this article.

Tobacco-related cardiovascular disease is the primary reason adults with schizophrenia die on average 28 years earlier than their peers in the U.S. general population.¹ To address this, clinicians need to prioritize smoking cessation and emphasize to patients with schizophrenia that quitting is the most important change they can make to improve their health. Here are 4 ways to help patients with schizophrenia quit smoking.

Provide hope, but be realistic. Most patients with schizophrenia who smoke want to quit; however, patients and clinicians alike have been discouraged by low quit rates and high relapse rates. Smoking often is viewed as one of the few remaining personal freedoms, as a lower priority than active psychiatric symptoms, or even as neuroprotective. By perpetuating these falsehoods and avoiding addressing smoking cessation, we are failing our patients.

With persistent engagement and use of effective pharmacotherapeutic interventions, smoking cessation is attainable and does not worsen psychiatric symptoms. Additionally, smoking cessation could save patients >$4,000 a year. It is crucial to make smoking cessation a priority at every appointment, and to offer patients hope and practical guidance through repeated attempts to quit.

Offer varenicline. For patients with schizophrenia, cessation counseling or behavioral interventions alone have a poor efficacy rate of approximately 5% (compared with 15% to 20% in the general population).² Varenicline is the most effective smoking cessation treatment; it increases cessation rates 5-fold among patients with schizophrenia.³ As demonstrated by the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES),⁴ varenicline does not lead to an increased risk of suicidality or serious neuropsychiatric adverse effects.

When starting a patient on varenicline, set a quit date 4 weeks from medication initiation. Individuals with schizophrenia often have a greater smoking burden and experience more intense symptoms of nicotine withdrawal. A 4-week period between medication initiation and the quit date will allow these patients to gradually experience reduced cravings and separate minor adverse effects of the medication from those of nicotine withdrawal. Concurrent prescription of nicotine replacement therapy (eg, patch, gum, lozenge, inhaler) also is safe and can assist in quit attempts.

Consider varenicline maintenance therapy. After a successful quit attempt, increase the likelihood of sustained cessation by continuing varenicline beyond 12 weeks. Varenicline can be used as a maintenance medication to prevent smoking relapse in patients with schizophrenia; when prescribed to these patients for an additional 3 months, it can reduce the relapse rate similarly to that seen in smokers in the general population.⁵

Adjust antipsychotic dosages. Tobacco smoke increases the activity of cytochrome P450 1A2, which metabolizes several antipsychotics. Thus, after successful smoking cessation, concentrations of clozapine, fluphenazine, haloperidol, and olanzapine may increase, and dose reduction may be warranted. Conversely, if a patient resumes smoking, dosages of these medications may need to be increased.

Acknowledgments

The authors thank Anne Eden Evins, MD, MPH, and Corinne Cather, PhD, for their input on this article.

Tobacco-related cardiovascular disease is the primary reason adults with schizophrenia die on average 28 years earlier than their peers in the U.S. general population.¹ To address this, clinicians need to prioritize smoking cessation and emphasize to patients with schizophrenia that quitting is the most important change they can make to improve their health. Here are 4 ways to help patients with schizophrenia quit smoking.

Provide hope, but be realistic. Most patients with schizophrenia who smoke want to quit; however, patients and clinicians alike have been discouraged by low quit rates and high relapse rates. Smoking often is viewed as one of the few remaining personal freedoms, as a lower priority than active psychiatric symptoms, or even as neuroprotective. By perpetuating these falsehoods and avoiding addressing smoking cessation, we are failing our patients.

With persistent engagement and use of effective pharmacotherapeutic interventions, smoking cessation is attainable and does not worsen psychiatric symptoms. Additionally, smoking cessation could save patients >$4,000 a year. It is crucial to make smoking cessation a priority at every appointment, and to offer patients hope and practical guidance through repeated attempts to quit.

Offer varenicline. For patients with schizophrenia, cessation counseling or behavioral interventions alone have a poor efficacy rate of approximately 5% (compared with 15% to 20% in the general population).² Varenicline is the most effective smoking cessation treatment; it increases cessation rates 5-fold among patients with schizophrenia.³ As demonstrated by the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES),⁴ varenicline does not lead to an increased risk of suicidality or serious neuropsychiatric adverse effects.

When starting a patient on varenicline, set a quit date 4 weeks from medication initiation. Individuals with schizophrenia often have a greater smoking burden and experience more intense symptoms of nicotine withdrawal. A 4-week period between medication initiation and the quit date will allow these patients to gradually experience reduced cravings and separate minor adverse effects of the medication from those of nicotine withdrawal. Concurrent prescription of nicotine replacement therapy (eg, patch, gum, lozenge, inhaler) also is safe and can assist in quit attempts.

Consider varenicline maintenance therapy. After a successful quit attempt, increase the likelihood of sustained cessation by continuing varenicline beyond 12 weeks. Varenicline can be used as a maintenance medication to prevent smoking relapse in patients with schizophrenia; when prescribed to these patients for an additional 3 months, it can reduce the relapse rate similarly to that seen in smokers in the general population.⁵

Adjust antipsychotic dosages. Tobacco smoke increases the activity of cytochrome P450 1A2, which metabolizes several antipsychotics. Thus, after successful smoking cessation, concentrations of clozapine, fluphenazine, haloperidol, and olanzapine may increase, and dose reduction may be warranted. Conversely, if a patient resumes smoking, dosages of these medications may need to be increased.

Acknowledgments

The authors thank Anne Eden Evins, MD, MPH, and Corinne Cather, PhD, for their input on this article.

Suicide is a common reality, accounting for approximately 800,000 deaths per year worldwide.¹ Properly assessing and minimizing suicide risk can be challenging. We are taught that lithium and clozapine can decrease suicidality, and many psychiatrists prescribe these medications with the firm, “evidence-based” belief that doing so reduces suicide risk. Paradoxically, what they in fact might be doing is the exact opposite; they may be giving high-risk patients the opportunity and the means to attempt suicide with a lethal amount of medication.

One patient diagnosed with a mood disorder who attempted suicide had a surprising point of view. After taking a large quantity of lithium in an attempt to overdose, she was admitted to the psychiatry unit. Upon discharge, the doctors gave her another handful of pills. She reported feeling that her physicians were giving her the means to attempt suicide again. This mindset forced me to rethink suicide risk, and I approached it as a math problem.

Operations research is a subfield of mathematics that tries to optimize one or more variables when multiple variables are in play. One example would be to maximize profit while minimizing cost. During World War II, operations research was used to decrease the number of munitions used to shoot down airplanes, and to sink submarines more efficiently.

Focusing on the patient who attempted suicide by overdose, the question was: If she was discharged from the psychiatry unit with a 30-day supply of medication, how lethal would that prescription be if deliberately taken all at once? And what can be done to minimize this suicide risk? Psychiatrists know that some medications are more dangerous than others, but few have performed quantitative analysis to determine the potential lethality of these medications. The math analysis did not involve multivariable calculus or differential equations, only multiplication and division. The results were eye-opening.

Calculating relative lethality

The lethal dose 50 (LD50) is the dose of a medication expressed in mg/kg that results in the death of 50% of the animals (usually rats) used in a controlled experiment. Open-source data for the LD50 of medications is provided by the manufacturers.

I tabulated this data for a wide range of psychiatric medications, including antipsychotics, mood stabilizers, and selective serotonin reuptake inhibitors, in a spreadsheet with columns for maximum daily dose, 30-day supply of the medication, LD50 in mg/kg, LD50 for a 60-kg subject, and percentage of the 30-day supply compared with LD50. I then sorted this data by relative lethality (for my complete data, see Figure 1 and the Table).

The rat dose in mg/kg was extrapolated to the human equivalent dose (HED) in mg/kg using a conversion factor of 6.2 (for a person who weighs 60 kg, the HED = LD50/6.2) as suggested by the FDA.² The dose for the first fatality is smaller than the HED, and toxicity occurs at even smaller doses. After simplifying all the terms, the formula for the HED-relative lethality is f(x) = 310x/LD50, where x is the daily dose of a medication prescribed for 30 days. This is the equation of a straight line with a slope inversely proportional to the LD50 of each medication and a y-axis intercept of 0. Each medication line shows that any dose rising above 100% on the y-axis is a quantum higher than the lethal dose.

Some commonly prescribed psychotropics are highly lethal

The relative lethality of many commonly prescribed psychiatric medications, including those frequently used to reduce suicidality, varies tremendously. For example, it is widely known that the first-line mood stabilizer lithium has a narrow therapeutic window and can rapidly become toxic. If a patient becomes dehydrated, even a normal lithium dose can be toxic or lethal. Lithium has a relative lethality of 1,063% (Figure 2). Clozapine has a relative lethality of 1,112%. Valproic acid has an even higher relative lethality of 1,666%. By contrast, aripiprazole and olanzapine have a relative lethality of 10% and 35%, respectively. For preventing suicide, prescribing a second-generation antipsychotic with a lower relative lethality may be preferable over prescribing a medication with a higher relative lethality.

According to U.S. poison control centers,³ from 2000 to 2014, there were 15,036 serious outcomes, including 61 deaths, associated with lithium use, and 6,109 serious outcomes, including 37 deaths, associated with valproic acid. In contrast, there were only 1,446 serious outcomes and no deaths associated with aripiprazole use.³ These outcomes may be underreported, but they are consistent with the mathematical model predicting that medications with a higher relative lethality will have higher morbidity and mortality outcomes, regardless of a patient’s intent to overdose.

Many psychiatrists have a preferred antidepressant, mood stabilizer, or antipsychotic, and may prescribe this medication to many of their patients based on familiarity with the agent or other factors. However, simple math can give the decision process of selecting a specific medication for a given patient a more quantitative basis.

Even a small reduction in suicide would save many lives

Ultimately, the math problem comes down to 4 minutes, which is approximately how long the brain can survive without oxygen. By prescribing medications with a lower relative lethality, or by prescribing a less-than-30-day supply of the most lethal medications, it may be possible to decrease overdose morbidity and mortality, and also buy enough time for emergency personnel to save a life. If simple math can put even a 1% dent in the rate of death from suicide, approximately 8,000 lives might be saved every year.

Suicide is a common reality, accounting for approximately 800,000 deaths per year worldwide.¹ Properly assessing and minimizing suicide risk can be challenging. We are taught that lithium and clozapine can decrease suicidality, and many psychiatrists prescribe these medications with the firm, “evidence-based” belief that doing so reduces suicide risk. Paradoxically, what they in fact might be doing is the exact opposite; they may be giving high-risk patients the opportunity and the means to attempt suicide with a lethal amount of medication.

One patient diagnosed with a mood disorder who attempted suicide had a surprising point of view. After taking a large quantity of lithium in an attempt to overdose, she was admitted to the psychiatry unit. Upon discharge, the doctors gave her another handful of pills. She reported feeling that her physicians were giving her the means to attempt suicide again. This mindset forced me to rethink suicide risk, and I approached it as a math problem.

Operations research is a subfield of mathematics that tries to optimize one or more variables when multiple variables are in play. One example would be to maximize profit while minimizing cost. During World War II, operations research was used to decrease the number of munitions used to shoot down airplanes, and to sink submarines more efficiently.

Focusing on the patient who attempted suicide by overdose, the question was: If she was discharged from the psychiatry unit with a 30-day supply of medication, how lethal would that prescription be if deliberately taken all at once? And what can be done to minimize this suicide risk? Psychiatrists know that some medications are more dangerous than others, but few have performed quantitative analysis to determine the potential lethality of these medications. The math analysis did not involve multivariable calculus or differential equations, only multiplication and division. The results were eye-opening.

Calculating relative lethality

The lethal dose 50 (LD50) is the dose of a medication expressed in mg/kg that results in the death of 50% of the animals (usually rats) used in a controlled experiment. Open-source data for the LD50 of medications is provided by the manufacturers.

I tabulated this data for a wide range of psychiatric medications, including antipsychotics, mood stabilizers, and selective serotonin reuptake inhibitors, in a spreadsheet with columns for maximum daily dose, 30-day supply of the medication, LD50 in mg/kg, LD50 for a 60-kg subject, and percentage of the 30-day supply compared with LD50. I then sorted this data by relative lethality (for my complete data, see Figure 1 and the Table).

The rat dose in mg/kg was extrapolated to the human equivalent dose (HED) in mg/kg using a conversion factor of 6.2 (for a person who weighs 60 kg, the HED = LD50/6.2) as suggested by the FDA.² The dose for the first fatality is smaller than the HED, and toxicity occurs at even smaller doses. After simplifying all the terms, the formula for the HED-relative lethality is f(x) = 310x/LD50, where x is the daily dose of a medication prescribed for 30 days. This is the equation of a straight line with a slope inversely proportional to the LD50 of each medication and a y-axis intercept of 0. Each medication line shows that any dose rising above 100% on the y-axis is a quantum higher than the lethal dose.

Some commonly prescribed psychotropics are highly lethal

The relative lethality of many commonly prescribed psychiatric medications, including those frequently used to reduce suicidality, varies tremendously. For example, it is widely known that the first-line mood stabilizer lithium has a narrow therapeutic window and can rapidly become toxic. If a patient becomes dehydrated, even a normal lithium dose can be toxic or lethal. Lithium has a relative lethality of 1,063% (Figure 2). Clozapine has a relative lethality of 1,112%. Valproic acid has an even higher relative lethality of 1,666%. By contrast, aripiprazole and olanzapine have a relative lethality of 10% and 35%, respectively. For preventing suicide, prescribing a second-generation antipsychotic with a lower relative lethality may be preferable over prescribing a medication with a higher relative lethality.

According to U.S. poison control centers,³ from 2000 to 2014, there were 15,036 serious outcomes, including 61 deaths, associated with lithium use, and 6,109 serious outcomes, including 37 deaths, associated with valproic acid. In contrast, there were only 1,446 serious outcomes and no deaths associated with aripiprazole use.³ These outcomes may be underreported, but they are consistent with the mathematical model predicting that medications with a higher relative lethality will have higher morbidity and mortality outcomes, regardless of a patient’s intent to overdose.

Many psychiatrists have a preferred antidepressant, mood stabilizer, or antipsychotic, and may prescribe this medication to many of their patients based on familiarity with the agent or other factors. However, simple math can give the decision process of selecting a specific medication for a given patient a more quantitative basis.

Even a small reduction in suicide would save many lives

Ultimately, the math problem comes down to 4 minutes, which is approximately how long the brain can survive without oxygen. By prescribing medications with a lower relative lethality, or by prescribing a less-than-30-day supply of the most lethal medications, it may be possible to decrease overdose morbidity and mortality, and also buy enough time for emergency personnel to save a life. If simple math can put even a 1% dent in the rate of death from suicide, approximately 8,000 lives might be saved every year.

Suicide is a common reality, accounting for approximately 800,000 deaths per year worldwide.¹ Properly assessing and minimizing suicide risk can be challenging. We are taught that lithium and clozapine can decrease suicidality, and many psychiatrists prescribe these medications with the firm, “evidence-based” belief that doing so reduces suicide risk. Paradoxically, what they in fact might be doing is the exact opposite; they may be giving high-risk patients the opportunity and the means to attempt suicide with a lethal amount of medication.

One patient diagnosed with a mood disorder who attempted suicide had a surprising point of view. After taking a large quantity of lithium in an attempt to overdose, she was admitted to the psychiatry unit. Upon discharge, the doctors gave her another handful of pills. She reported feeling that her physicians were giving her the means to attempt suicide again. This mindset forced me to rethink suicide risk, and I approached it as a math problem.

Operations research is a subfield of mathematics that tries to optimize one or more variables when multiple variables are in play. One example would be to maximize profit while minimizing cost. During World War II, operations research was used to decrease the number of munitions used to shoot down airplanes, and to sink submarines more efficiently.

Focusing on the patient who attempted suicide by overdose, the question was: If she was discharged from the psychiatry unit with a 30-day supply of medication, how lethal would that prescription be if deliberately taken all at once? And what can be done to minimize this suicide risk? Psychiatrists know that some medications are more dangerous than others, but few have performed quantitative analysis to determine the potential lethality of these medications. The math analysis did not involve multivariable calculus or differential equations, only multiplication and division. The results were eye-opening.

Calculating relative lethality

The lethal dose 50 (LD50) is the dose of a medication expressed in mg/kg that results in the death of 50% of the animals (usually rats) used in a controlled experiment. Open-source data for the LD50 of medications is provided by the manufacturers.

I tabulated this data for a wide range of psychiatric medications, including antipsychotics, mood stabilizers, and selective serotonin reuptake inhibitors, in a spreadsheet with columns for maximum daily dose, 30-day supply of the medication, LD50 in mg/kg, LD50 for a 60-kg subject, and percentage of the 30-day supply compared with LD50. I then sorted this data by relative lethality (for my complete data, see Figure 1 and the Table).

The rat dose in mg/kg was extrapolated to the human equivalent dose (HED) in mg/kg using a conversion factor of 6.2 (for a person who weighs 60 kg, the HED = LD50/6.2) as suggested by the FDA.² The dose for the first fatality is smaller than the HED, and toxicity occurs at even smaller doses. After simplifying all the terms, the formula for the HED-relative lethality is f(x) = 310x/LD50, where x is the daily dose of a medication prescribed for 30 days. This is the equation of a straight line with a slope inversely proportional to the LD50 of each medication and a y-axis intercept of 0. Each medication line shows that any dose rising above 100% on the y-axis is a quantum higher than the lethal dose.

Some commonly prescribed psychotropics are highly lethal

The relative lethality of many commonly prescribed psychiatric medications, including those frequently used to reduce suicidality, varies tremendously. For example, it is widely known that the first-line mood stabilizer lithium has a narrow therapeutic window and can rapidly become toxic. If a patient becomes dehydrated, even a normal lithium dose can be toxic or lethal. Lithium has a relative lethality of 1,063% (Figure 2). Clozapine has a relative lethality of 1,112%. Valproic acid has an even higher relative lethality of 1,666%. By contrast, aripiprazole and olanzapine have a relative lethality of 10% and 35%, respectively. For preventing suicide, prescribing a second-generation antipsychotic with a lower relative lethality may be preferable over prescribing a medication with a higher relative lethality.

According to U.S. poison control centers,³ from 2000 to 2014, there were 15,036 serious outcomes, including 61 deaths, associated with lithium use, and 6,109 serious outcomes, including 37 deaths, associated with valproic acid. In contrast, there were only 1,446 serious outcomes and no deaths associated with aripiprazole use.³ These outcomes may be underreported, but they are consistent with the mathematical model predicting that medications with a higher relative lethality will have higher morbidity and mortality outcomes, regardless of a patient’s intent to overdose.

Many psychiatrists have a preferred antidepressant, mood stabilizer, or antipsychotic, and may prescribe this medication to many of their patients based on familiarity with the agent or other factors. However, simple math can give the decision process of selecting a specific medication for a given patient a more quantitative basis.

Even a small reduction in suicide would save many lives

Ultimately, the math problem comes down to 4 minutes, which is approximately how long the brain can survive without oxygen. By prescribing medications with a lower relative lethality, or by prescribing a less-than-30-day supply of the most lethal medications, it may be possible to decrease overdose morbidity and mortality, and also buy enough time for emergency personnel to save a life. If simple math can put even a 1% dent in the rate of death from suicide, approximately 8,000 lives might be saved every year.

In response to Dr. Mark Zimmerman’s article, “Improving the recognition of borderline personality disorder” (Current Psychiatry. October 2017, p. 13-19), I think the topic of improving the diagnosis of borderline personality disorder (BPD) requires us to examine our own biases and stigma toward this diagnosis. Let’s be honest: many psychiatrists don’t make the diagnosis because they don’t want to give their patient that diagnosis and they don’t want to treat a patient with that diagnosis. Evidence suggests that a great proportion of stigma aimed at BPD is initiated by mental health professionals.^1,2

Why all the stigma? Because mental health professionals don’t have complete information. The assumption used to be that BPD was “intractable” with no treatment. Even if this were true, it still would not be a reason to fail to disclose a diagnosis, because in other fields of medicine, the concept of “therapeutic privilege” fell by the wayside long ago. However, we now know that in many individuals with BPD, symptoms improve over time, and there are several effective treatments.

In DSM-II, published in 1968, obsessive-compulsive disorder (OCD) was characterized as an “obsessive compulsive neurosis.” It was not reclassified as the current OCD diagnosis until DSM-III-R was published in 1987, after the FDA approved clomipramine. Why is this important? Because once people realized that there was a treatment, they started acknowledging OCD more often.

The first step in addressing the stigma toward BPD is that mental health professionals must recognize their own bias toward this diagnosis. We must be re-educated that this diagnosis carries hope, symptoms improve, and that there are effective treatments. This is how professionals will increase the recognition of BPD.

Michael Shapiro, MD, FAPA
Assistant Professor and Compliance Officer
Department of Psychiatry
University of Florida
Clinic Director
UF Child and Adolescent Psychiatry Clinic at Springhill Health Center
Gainesville, Florida

References

1. Unruh BT, Gunderson JG. “Good enough” psychiatric residency training in borderline personality disorder: challenges, choice points, and a model generalist curriculum. Harv Rev Psychiatry. 2016;24(5):367-377.
2. Sheehan L, Nieweglowski K, Corrigan P. The stigma of personality disorders. Curr Psychiatry Rep. 2016;18(1):11.

Continue to: The author responds

The author responds

I agree with Dr. Shapiro that stigma by mental health clinicians contributes to the underdiagnosis of BPD. Mental health professions often hold a negative view of patients with personality disorders, particularly those with BPD, and see these patients as being more difficult to treat.^1-3 They are the patients that some clinicians are reluctant to treat.^3,4 Clinicians perceive patients with personality disorders as less mentally ill, more manipulative, and more able to control their behavior than patients with other psychiatric disorders.^3,5 Consistent with this, clinicians have less sympathetic attitudes and behave less empathically toward patients with BPD.^5,6 The term “borderline” also is sometimes used pejoratively to describe patients.¹

As I described in my article, there are several possible reasons BPD is under­diagnosed. Foremost is that mood disorders, anxiety disorders, and substance use disorders are common in patients with BPD, and the symptoms of these other disorders are typically patients’ chief concerns when they present for treatment. Patients with BPD do not usually report the features of BPD—such as abandonment fears, chronic feelings of emptiness, or an identity disturbance—as their chief concerns. If they did, BPD would likely be easier to recognize. On a related note, clinicians do not have the time, or do not take the time, to conduct a thorough enough evaluation to diagnose BPD when it occurs in a patient who presents for treatment of a mood disorder, anxiety disorder, or substance use disorder. Our clinical research group found that when psychiatrists are presented with the results of a semi-structured interview, BPD is much more frequently diagnosed.⁷ Such a finding would not be expected if stigma was the primary or sole reason for underdiagnosis.

Dr. Shapiro highlights the clinical consequence of underrecognition and underdiagnosis: the underutilization of empirically supported psychotherapies for BPD. A corollary of underdiagnosing BPD is overdiagnosis of bipolar disorder and overprescription of medication.⁸

There are other consequences of bias and stigma toward BPD. Despite the high levels of psychosocial morbidity, reduced health-related quality of life, high utilization of services, and excess mortality associated with BPD, this disorder is not included in the Global Burden of Disease Study. Thus, the public health significance of BPD is less fully appreciated. Finally, there is evidence that the level of funding for research from the National Institutes of Health is not commensurate with the level of psychosocial morbidity, mortality, and health expenditures associated with the disorder.⁹ Thus, the stigma toward BPD exists in both clinical and research communities.

Mark Zimmerman, MD
Professor of Psychiatry and Human Behavior
Warren Alpert Medical School of Brown University
Rhode Island Hospital
Providence, Rhode Island

References

1. Cleary M, Siegfried N, Walter G. Experience, knowledge and attitudes of mental health staff regarding clients with a borderline personality disorder. Int J Ment Health Nurs. 2002;11(3):186-191.
2. Gallop R, Lancee WJ, Garfinkel P. How nursing staff respond to the label “borderline personality disorder.” Hosp Community Psychiatry. 1989;40(8):815-819.
3. Lewis G, Appleby L. Personality disorder: the patients psychiatrists dislike. Br J Psychiatry. 1988;153:44-49.
4. Black DW, Pfohl B, Blum N, et al. Attitudes toward borderline personality disorder: a survey of 706 mental health clinicians. CNS Spectr. 2011;16(3):67-74.
5. Markham D, Trower P. The effects of the psychiatric label ‘borderline personality disorder’ on nursing staff’s perceptions and causal attributions for challenging behaviours. Br J Clin Psychol. 2003;42(pt 3):243-256.
6. Fraser K, Gallop R. Nurses’ confirming/disconfirming responses to patients diagnosed with borderline personality disorder. Arch Psychiatr Nurs. 1993;7(6):336-341.
7. Zimmerman M, Mattia JI. Differences between clinical and research practices in diagnosing borderline personality disorder. Am J Psychiatry. 1999;156(10):1570-1574.
8. Zimmerman M, Ruggero CJ, Chelminski I, et al. Is bipolar disorder overdiagnosed? J Clin Psychiatry. 2008;69(6):935-940.
9. Zimmerman M, Gazarian D. Is research on borderline personality disorder underfunded by the National Institute of Health? Psychiatry Res. 2014;220(3):941-944.

In response to Dr. Mark Zimmerman’s article, “Improving the recognition of borderline personality disorder” (Current Psychiatry. October 2017, p. 13-19), I think the topic of improving the diagnosis of borderline personality disorder (BPD) requires us to examine our own biases and stigma toward this diagnosis. Let’s be honest: many psychiatrists don’t make the diagnosis because they don’t want to give their patient that diagnosis and they don’t want to treat a patient with that diagnosis. Evidence suggests that a great proportion of stigma aimed at BPD is initiated by mental health professionals.^1,2

Why all the stigma? Because mental health professionals don’t have complete information. The assumption used to be that BPD was “intractable” with no treatment. Even if this were true, it still would not be a reason to fail to disclose a diagnosis, because in other fields of medicine, the concept of “therapeutic privilege” fell by the wayside long ago. However, we now know that in many individuals with BPD, symptoms improve over time, and there are several effective treatments.

In DSM-II, published in 1968, obsessive-compulsive disorder (OCD) was characterized as an “obsessive compulsive neurosis.” It was not reclassified as the current OCD diagnosis until DSM-III-R was published in 1987, after the FDA approved clomipramine. Why is this important? Because once people realized that there was a treatment, they started acknowledging OCD more often.

The first step in addressing the stigma toward BPD is that mental health professionals must recognize their own bias toward this diagnosis. We must be re-educated that this diagnosis carries hope, symptoms improve, and that there are effective treatments. This is how professionals will increase the recognition of BPD.

Michael Shapiro, MD, FAPA
Assistant Professor and Compliance Officer
Department of Psychiatry
University of Florida
Clinic Director
UF Child and Adolescent Psychiatry Clinic at Springhill Health Center
Gainesville, Florida

References

1. Unruh BT, Gunderson JG. “Good enough” psychiatric residency training in borderline personality disorder: challenges, choice points, and a model generalist curriculum. Harv Rev Psychiatry. 2016;24(5):367-377.
2. Sheehan L, Nieweglowski K, Corrigan P. The stigma of personality disorders. Curr Psychiatry Rep. 2016;18(1):11.

Continue to: The author responds

The author responds

I agree with Dr. Shapiro that stigma by mental health clinicians contributes to the underdiagnosis of BPD. Mental health professions often hold a negative view of patients with personality disorders, particularly those with BPD, and see these patients as being more difficult to treat.^1-3 They are the patients that some clinicians are reluctant to treat.^3,4 Clinicians perceive patients with personality disorders as less mentally ill, more manipulative, and more able to control their behavior than patients with other psychiatric disorders.^3,5 Consistent with this, clinicians have less sympathetic attitudes and behave less empathically toward patients with BPD.^5,6 The term “borderline” also is sometimes used pejoratively to describe patients.¹

As I described in my article, there are several possible reasons BPD is under­diagnosed. Foremost is that mood disorders, anxiety disorders, and substance use disorders are common in patients with BPD, and the symptoms of these other disorders are typically patients’ chief concerns when they present for treatment. Patients with BPD do not usually report the features of BPD—such as abandonment fears, chronic feelings of emptiness, or an identity disturbance—as their chief concerns. If they did, BPD would likely be easier to recognize. On a related note, clinicians do not have the time, or do not take the time, to conduct a thorough enough evaluation to diagnose BPD when it occurs in a patient who presents for treatment of a mood disorder, anxiety disorder, or substance use disorder. Our clinical research group found that when psychiatrists are presented with the results of a semi-structured interview, BPD is much more frequently diagnosed.⁷ Such a finding would not be expected if stigma was the primary or sole reason for underdiagnosis.

Dr. Shapiro highlights the clinical consequence of underrecognition and underdiagnosis: the underutilization of empirically supported psychotherapies for BPD. A corollary of underdiagnosing BPD is overdiagnosis of bipolar disorder and overprescription of medication.⁸

There are other consequences of bias and stigma toward BPD. Despite the high levels of psychosocial morbidity, reduced health-related quality of life, high utilization of services, and excess mortality associated with BPD, this disorder is not included in the Global Burden of Disease Study. Thus, the public health significance of BPD is less fully appreciated. Finally, there is evidence that the level of funding for research from the National Institutes of Health is not commensurate with the level of psychosocial morbidity, mortality, and health expenditures associated with the disorder.⁹ Thus, the stigma toward BPD exists in both clinical and research communities.

Mark Zimmerman, MD
Professor of Psychiatry and Human Behavior
Warren Alpert Medical School of Brown University
Rhode Island Hospital
Providence, Rhode Island

References

1. Cleary M, Siegfried N, Walter G. Experience, knowledge and attitudes of mental health staff regarding clients with a borderline personality disorder. Int J Ment Health Nurs. 2002;11(3):186-191.
2. Gallop R, Lancee WJ, Garfinkel P. How nursing staff respond to the label “borderline personality disorder.” Hosp Community Psychiatry. 1989;40(8):815-819.
3. Lewis G, Appleby L. Personality disorder: the patients psychiatrists dislike. Br J Psychiatry. 1988;153:44-49.
4. Black DW, Pfohl B, Blum N, et al. Attitudes toward borderline personality disorder: a survey of 706 mental health clinicians. CNS Spectr. 2011;16(3):67-74.
5. Markham D, Trower P. The effects of the psychiatric label ‘borderline personality disorder’ on nursing staff’s perceptions and causal attributions for challenging behaviours. Br J Clin Psychol. 2003;42(pt 3):243-256.
6. Fraser K, Gallop R. Nurses’ confirming/disconfirming responses to patients diagnosed with borderline personality disorder. Arch Psychiatr Nurs. 1993;7(6):336-341.
7. Zimmerman M, Mattia JI. Differences between clinical and research practices in diagnosing borderline personality disorder. Am J Psychiatry. 1999;156(10):1570-1574.
8. Zimmerman M, Ruggero CJ, Chelminski I, et al. Is bipolar disorder overdiagnosed? J Clin Psychiatry. 2008;69(6):935-940.
9. Zimmerman M, Gazarian D. Is research on borderline personality disorder underfunded by the National Institute of Health? Psychiatry Res. 2014;220(3):941-944.

In response to Dr. Mark Zimmerman’s article, “Improving the recognition of borderline personality disorder” (Current Psychiatry. October 2017, p. 13-19), I think the topic of improving the diagnosis of borderline personality disorder (BPD) requires us to examine our own biases and stigma toward this diagnosis. Let’s be honest: many psychiatrists don’t make the diagnosis because they don’t want to give their patient that diagnosis and they don’t want to treat a patient with that diagnosis. Evidence suggests that a great proportion of stigma aimed at BPD is initiated by mental health professionals.^1,2

Why all the stigma? Because mental health professionals don’t have complete information. The assumption used to be that BPD was “intractable” with no treatment. Even if this were true, it still would not be a reason to fail to disclose a diagnosis, because in other fields of medicine, the concept of “therapeutic privilege” fell by the wayside long ago. However, we now know that in many individuals with BPD, symptoms improve over time, and there are several effective treatments.

In DSM-II, published in 1968, obsessive-compulsive disorder (OCD) was characterized as an “obsessive compulsive neurosis.” It was not reclassified as the current OCD diagnosis until DSM-III-R was published in 1987, after the FDA approved clomipramine. Why is this important? Because once people realized that there was a treatment, they started acknowledging OCD more often.

The first step in addressing the stigma toward BPD is that mental health professionals must recognize their own bias toward this diagnosis. We must be re-educated that this diagnosis carries hope, symptoms improve, and that there are effective treatments. This is how professionals will increase the recognition of BPD.

Michael Shapiro, MD, FAPA
Assistant Professor and Compliance Officer
Department of Psychiatry
University of Florida
Clinic Director
UF Child and Adolescent Psychiatry Clinic at Springhill Health Center
Gainesville, Florida

References

1. Unruh BT, Gunderson JG. “Good enough” psychiatric residency training in borderline personality disorder: challenges, choice points, and a model generalist curriculum. Harv Rev Psychiatry. 2016;24(5):367-377.
2. Sheehan L, Nieweglowski K, Corrigan P. The stigma of personality disorders. Curr Psychiatry Rep. 2016;18(1):11.

Continue to: The author responds

The author responds

I agree with Dr. Shapiro that stigma by mental health clinicians contributes to the underdiagnosis of BPD. Mental health professions often hold a negative view of patients with personality disorders, particularly those with BPD, and see these patients as being more difficult to treat.^1-3 They are the patients that some clinicians are reluctant to treat.^3,4 Clinicians perceive patients with personality disorders as less mentally ill, more manipulative, and more able to control their behavior than patients with other psychiatric disorders.^3,5 Consistent with this, clinicians have less sympathetic attitudes and behave less empathically toward patients with BPD.^5,6 The term “borderline” also is sometimes used pejoratively to describe patients.¹

As I described in my article, there are several possible reasons BPD is under­diagnosed. Foremost is that mood disorders, anxiety disorders, and substance use disorders are common in patients with BPD, and the symptoms of these other disorders are typically patients’ chief concerns when they present for treatment. Patients with BPD do not usually report the features of BPD—such as abandonment fears, chronic feelings of emptiness, or an identity disturbance—as their chief concerns. If they did, BPD would likely be easier to recognize. On a related note, clinicians do not have the time, or do not take the time, to conduct a thorough enough evaluation to diagnose BPD when it occurs in a patient who presents for treatment of a mood disorder, anxiety disorder, or substance use disorder. Our clinical research group found that when psychiatrists are presented with the results of a semi-structured interview, BPD is much more frequently diagnosed.⁷ Such a finding would not be expected if stigma was the primary or sole reason for underdiagnosis.

Dr. Shapiro highlights the clinical consequence of underrecognition and underdiagnosis: the underutilization of empirically supported psychotherapies for BPD. A corollary of underdiagnosing BPD is overdiagnosis of bipolar disorder and overprescription of medication.⁸

There are other consequences of bias and stigma toward BPD. Despite the high levels of psychosocial morbidity, reduced health-related quality of life, high utilization of services, and excess mortality associated with BPD, this disorder is not included in the Global Burden of Disease Study. Thus, the public health significance of BPD is less fully appreciated. Finally, there is evidence that the level of funding for research from the National Institutes of Health is not commensurate with the level of psychosocial morbidity, mortality, and health expenditures associated with the disorder.⁹ Thus, the stigma toward BPD exists in both clinical and research communities.

Mark Zimmerman, MD
Professor of Psychiatry and Human Behavior
Warren Alpert Medical School of Brown University
Rhode Island Hospital
Providence, Rhode Island

References

1. Cleary M, Siegfried N, Walter G. Experience, knowledge and attitudes of mental health staff regarding clients with a borderline personality disorder. Int J Ment Health Nurs. 2002;11(3):186-191.
2. Gallop R, Lancee WJ, Garfinkel P. How nursing staff respond to the label “borderline personality disorder.” Hosp Community Psychiatry. 1989;40(8):815-819.
3. Lewis G, Appleby L. Personality disorder: the patients psychiatrists dislike. Br J Psychiatry. 1988;153:44-49.
4. Black DW, Pfohl B, Blum N, et al. Attitudes toward borderline personality disorder: a survey of 706 mental health clinicians. CNS Spectr. 2011;16(3):67-74.
5. Markham D, Trower P. The effects of the psychiatric label ‘borderline personality disorder’ on nursing staff’s perceptions and causal attributions for challenging behaviours. Br J Clin Psychol. 2003;42(pt 3):243-256.
6. Fraser K, Gallop R. Nurses’ confirming/disconfirming responses to patients diagnosed with borderline personality disorder. Arch Psychiatr Nurs. 1993;7(6):336-341.
7. Zimmerman M, Mattia JI. Differences between clinical and research practices in diagnosing borderline personality disorder. Am J Psychiatry. 1999;156(10):1570-1574.
8. Zimmerman M, Ruggero CJ, Chelminski I, et al. Is bipolar disorder overdiagnosed? J Clin Psychiatry. 2008;69(6):935-940.
9. Zimmerman M, Gazarian D. Is research on borderline personality disorder underfunded by the National Institute of Health? Psychiatry Res. 2014;220(3):941-944.

Point-of-care ultrasound (POCUS) has been gaining greater traction in recent years as a way to quickly (and cost-effectively) assess for conditions including systolic dysfunction, pleural effusion, abdominal aortic aneurysms (AAAs), and deep vein thrombosis (DVT). It involves limited and specific ultrasound protocols performed at the bedside by the health care provider who is trying to answer a specific question and, thus, help guide treatment of the patient.

POCUS was first widely used by emergency physicians starting in the early 1990s with the widespread adoption of the Focused Assessment with Sonography in Trauma (FAST) scan.^1,2 Since that time, POCUS has expanded beyond trauma applications and into family medicine.

One study assessed physicians’ perceptions of POCUS after its integration into a military family medicine clinic. The study showed that physicians perceived POCUS to be relatively easy to use, not overly time consuming, and of high value to the practice.³ In fact, the literature tells us that POCUS can help decrease the cost of health care and improve outcomes,^4-7 while requiring a relatively brief training period.

If residencies are any indication, POCUS may be headed your way

Ultrasound units are becoming smaller and more affordable, and medical schools are increasingly incorporating ultrasound curricula into medical student training.⁸ As of 2016, only 6% of practicing FPs reported using non-obstetric POCUS in their practices.⁹ Similarly, a survey from 2015 reported that only 2% of family medicine residency programs had established POCUS curricula.¹⁰ However, 50% of respondents in the 2015 survey reported early-stage development or interest in developing a POCUS curriculum.

Since then a validated family medicine residency curriculum has been published,¹¹ and the American Academy of Family Physicians (AAFP) recently released a POCUS Curriculum Guideline for residencies (https://www.aafp.org/dam/AAFP/documents/medical_education_residency/program_directors/Reprint290D_POCUS.pdf).

[polldaddy:9928416]

The potential applications of POCUS in family medicine are numerous and have been reviewed in several recent publications.^12,13 In this article, we will review the evidence for the use of POCUS in 4 areas: the cardiovascular exam (FIGURES 1 and 2), the lung exam (FIGURES 3-6), the screening exam for AAAs (FIGURE 7), and the evaluation for DVT (FIGURES 8 and 9). (Obstetric and musculoskeletal applications have been sufficiently covered elsewhere.^14-17) For all of these applications, POCUS is safe, accurate, and beneficial and can be performed with a relatively small amount of training by non-radiology specialists, including FPs (TABLEs 1 and 2).

Just 2 hours of cardio POCUS training enhanced Dx accuracy

The American Society of Echocardiography (ASE) issued an expert consensus statement for focused cardiac ultrasound in 2013.¹⁸ The guideline supports non-cardiologists utilizing POCUS to assess for pericardial effusion and right and left ventricular enlargement, as well as to review global cardiac systolic function and intravascular volume status. Cardiovascular POCUS protocols are relatively easy to learn; even small amounts of training and practice can yield competency.

Point-of-care ultrasound is safe, accurate, and beneficial and can be performed with a relatively small amount of training by family physicians.

For example, a 2013 study showed that after 2 hours of training with a pocket ultrasound device, medical students and junior physicians inexperienced with POCUS were able to improve their diagnostic accuracy for heart failure from 50% to 75%.¹⁹ In another study, internal medicine residents with limited cardiac ultrasound training (ie, 20 practice exams) were able to detect decreased left ventricular ejection fraction using a handheld ultrasound device with 94% sensitivity and specificity in patients admitted to the hospital with acute decompensated heart failure.²⁰ Similarly, after only 8 hours of training, a group of Norwegian general practitioners were able to obtain measurements of systolic function with a pocket ultrasound device that were not statistically different from a cardiologist’s measurements.²¹

In another study, rural FPs attended a 4-day course and then performed focused cardiac ultrasounds on primary care patients with a clinical indication for an echocardiogram.²² The scans were uploaded to a Web-based program for remote interpretation by a cardiologist. There was high concordance between the FPs’ interpretations of the focused cardiac ultrasounds and the cardiologist’s interpretations. Only 32% of the patients in the study group required a formal follow-up echocardiogram.

Kimura et al published a POCUS protocol for the rapid assessment of patients with heart failure, called the Cardiopulmonary Limited Ultrasound Exam (CLUE).²³ The CLUE protocol utilizes 4 views to assess left ventricular systolic and diastolic function along with signs of pulmonary edema or systemic volume overload (TABLE 3²³). The presence of pulmonary edema or a plethoric inferior vena cava (IVC) was highly prognostic of in-hospital mortality. The CLUE protocol has been successfully used by novices including internal medicine residents after brief training (ie, up to 60 supervised scans) and can be performed in less than 5 minutes.^24,25

More sensitive, specific than x-rays for pulmonary diagnoses

The chest x-ray has traditionally been the imaging modality of choice to evaluate primary care pulmonary complaints. However, POCUS can be more sensitive and specific than a chest x-ray for evaluating several pulmonary diagnoses including pleural effusion, pneumonia, and pulmonary edema.

Pleural effusion can be difficult to detect with a physical exam alone. A systematic review showed that the physical exam is not sensitive for effusions <300 mL and can have even lower utility in obese patients.²⁸ While an upright lateral chest x-ray can accurately detect effusions as small as 50 mL, portable x-rays have sensitivities of only 53% to 71% for small- or moderate-sized effusions.^29,30 Ultrasound, however, has a sensitivity of 97% for small effusions.³¹

A 2016 meta-analysis showed that POCUS had a pooled sensitivity and specificity of 94% and 98%, respectively, for pleural effusions, while chest x-ray had a pooled sensitivity and specificity of 51% and 91%, respectively, when compared with computed tomography (CT) and expert sonography.³² POCUS evaluation for pleural effusion is technically simple, and at least one study showed that even novice users can achieve high diagnostic accuracy after only 3 hours of training.³³

Pneumonia is the eighth leading cause of death in the United States and the single leading cause of infectious disease death in children worldwide.^34-36 Pneumonia is a difficult diagnosis to make based on a history and physical examination alone, and the Infectious Diseases Society of America recommends diagnostic imaging to make the diagnosis.³⁷

The adult and pediatric literature clearly demonstrate that lung ultrasound is accurate at diagnosing pneumonia. In a 2015 meta-analysis of the pediatric literature, lung ultrasound had a sensitivity of 96% and a specificity of 93% and positive and negative likelihood ratios of 15.3 and 0.06, respectively.³⁸ In adults, a 2016 meta-analysis of lung ultrasound showed a pooled sensitivity and specificity of 90% and 88%, respectively, with positive and negative likelihood ratios of 6.6 and 0.08, respectively.³⁹

In 2015, a prospective study compared the accuracy of lung ultrasound and chest x-ray using CT as the gold standard.⁴⁰ Lung ultrasound had a significantly better sensitivity of 82% compared to a sensitivity of 64% for chest x-ray. Specificities were comparable at 94% for ultrasound and 90% for chest x-ray.⁴⁰

At least one study found novice sonographers to be accurate with lung POCUS for the diagnosis of pneumonia after only two 90-minute training sessions.⁴¹ Moreover, ultrasound has a more favorable safety profile, greater portability, and lower cost compared with chest x-ray and CT.

Pulmonary edema. Lung ultrasound can identify interstitial pulmonary edema via artifacts called B lines, which are produced by the reverberation of sound waves from the pleura due to the widening of the fluid-filled interlobular septa. These are distinctly different from the A-line pattern of repeating horizontal lines that is seen with normal lungs, making lung ultrasound more accurate than chest x-ray for identification of pulmonary edema.^42,43 When final diagnosis via blinded chart review is used as the reference standard, bilateral B lines on a lung ultrasound image have a sensitivity of 86% to 100% and a specificity of 92% to 98% for the diagnosis of pulmonary edema compared to chest x-ray’s sensitivity of 56.9% and specificity of 89.2%.⁴⁴ There is also a linear correlation between the number of B lines present and the extent of pulmonary edema.^42,45,46 The number of B lines decreases in real time as volume is removed in dialysis patients.⁴⁷

POCUS evaluation for B lines can be learned very quickly. Exams of novices who have performed only 5 prior exams correlate highly with those of experts who have performed more than 100 exams.⁴⁸

Simple, efficient screening method for abdominal aortic aneurysm

AAAs are present in up to 7% of men over the age of 50.⁴⁹ The mortality rate of a ruptured AAA is as high as 80% to 95%.⁵⁰ There is, however, a long prodromal period when interventions can make a significant difference, which is why accurate screening is so important.

AAA screening with ultrasound has been shown to decrease mortality.⁵¹ The current recommendation of the US Preventive Services Task Force (USPSTF) is a one-time AAA screening for all men ages 65 to 75 years who have ever smoked (Grade B).⁵² Despite the recommendations of the USPSTF, screening rates are low. One study found that only 9% of eligible patients in primary care practices received appropriate screening.⁵¹

Ultrasound performed by specialists is known to be an excellent screening test for AAA with a sensitivity of 98.9% and a specificity of 99.9%.⁵³ POCUS use by emergency medicine physicians for the evaluation of symptomatic AAA is well established in the literature. A meta-analysis including 7 studies and 655 patients showed a pooled sensitivity of 99% and a specificity of 98%.⁵⁴ Multiple studies also support primary care physicians performing POCUS AAA screening in the clinic setting.

For example, a 2012 prospective, observational study performed in Canada compared office-based ultrasound screening exams performed by a rural FP to scans performed in the hospital on the same patients.⁵⁵ The physician completed 50 training examinations. The average discrepancy in aorta diameters between the 2 was only 2 mm, which is clinically insignificant, and the office-based scans had a sensitivity and specificity of 100%.

Similarly, a second FP study performed in Barcelona, showed that an FP who performed POCUS AAA screening had 100% concordance with a radiologist.⁵⁶ Additionally, POCUS screening for AAA was not time consuming; it was performed in under 4 minutes per patient.^55,57

Ruling out DVT

DVT is a relatively rare occurrence in the ambulatory setting. However, patients who present with a painful, swollen lower extremity are much more common, and DVT must be considered and ruled out in these situations.

Although isolated distal DVTs that occur in the calf veins are usually self-limited and have a very low risk of embolization, they can progress to proximal DVTs of the thigh veins up to 20% of time.^58,59 Similarly, thrombophlebitis of the superficial lower extremity veins rarely embolizes, but can progress to a proximal DVT, especially if large segments are involved or if the segments are within 5 cm of the junction to the deep venous system.⁵⁹ The risk of missing a proximal leg DVT is high because embolization occurs up to 60% of the time if the DVT is left untreated.⁶⁰

The current standard for diagnosis of DVT is the lower extremity Doppler ultrasound examination, but obtaining same-day Doppler evaluations can be difficult in the ambulatory setting. In these instances, the American College of Chest Physicians (ACCP) recommends that even low-risk patients receive anticoagulation pending the evaluation if it cannot be obtained in the first 24 hours.⁵⁹ This approach not only increases the cost of care, but also exposes patients—many of whom will not be diagnosed with thrombosis in the end—to the risks of anticoagulation.

D-dimer blood tests have drawbacks, too. While a negative high-sensitivity D-dimer blood test in a patient with a low pre-test probability of DVT can effectively rule out a DVT, laboratory testing is not always immediately available in the ambulatory setting either.⁶¹ Additionally, false-positive rates are high, and positive D-dimer exams still require evaluation by Doppler ultrasound.

Given these limitations, performing an ultrasound at the bedside or in the exam room can allow for more timely and cost-effective care. In fact, research shows that a limited ultrasound, called the 2-region compression exam, which follows along the course of the common femoral vein and popliteal vein only, ignoring the femoral and calf veins, is highly accurate in assessing for proximal leg DVTs. As such, it has been adopted for POCUS use by emergency medicine physicians.⁶²

Multiple studies show that physicians with minimal training can perform the 2-region compression exam with a high degree of accuracy when full-leg Doppler ultrasound was used as the gold standard.^63,64 In these studies, hands-on training times ranged from only 10 minutes to 5 hours, and the exam could be performed in less than 4 minutes. A systematic review of 6 studies comparing emergency physician-performed ultrasound with radiology-performed ultrasound calculated an overall sensitivity of 0.95 (95% CI, 0.87-0.99) and specificity of 0.96 (95% CI, 0.87-0.99) for those performed by emergency physicians.⁶⁵

The main concern with the 2-region compression exam is that it can miss a distal leg DVT. As stated earlier, distal DVTs are relatively benign and tend to resolve without treatment; however, up to 20% can progress to become a dangerous proximal leg DVT.⁵⁸ Researchers have validated several methods by prospective trials to address this limitation.

Point-of-care ultrasound screening for abdominal aortic aneurysm can be performed in less than 4 minutes.

Specifically, researchers have demonstrated that patients with a low pre-test probability of DVT per the Wells scoring system could have DVT effectively ruled out with a single 2-region compression ultrasound without further evaluation.⁶⁶ In another study, researchers evaluated all patients (regardless of pretest probability) with a 2-point compression exam and found that those with negative exams could be followed with a second exam in 7 to 10 days without initiating anticoagulation. If the second one was negative, no further evaluation was needed.^67,68

And finally, researchers demonstrated that a negative 2-point compression ultrasound in combination with a concurrent negative D-dimer test was effective at ruling out DVT, regardless of pre-test probability.^69,70

A preferred approach

Given this data and the fact that in the ambulatory setting it is often easier and faster to perform a 2-region compression examination than to obtain a D-dimer laboratory test or a formal full-leg Doppler ultrasound, what follows is our preferred approach to a patient with suspected DVT in the outpatient setting (FIGURE 10).

We first assess pre-test probability using the Wells scoring system. We then perform the 2-region compression ultrasound. If the patient has low pre-test risk according to the Wells score, we rule out DVT. If the patient has moderate or high risk with a negative 2-region compression ultrasound, the patient gets a D-dimer test. If the D-dimer test is negative, we rule out DVT. If the D-dimer test is positive, we schedule the patient for a repeat 2-region compression ultrasound in 7 to 10 days. If at any time the 2-region compression evaluation is positive, we treat the patient for DVT.

CORRESPONDENCE
Paul Bornemann, MD, Palmetto Health Family Medicine Residency, Department of Family and Preventive Medicine, University of South Carolina School of Medicine, 3209 Colonial Drive, Columbia, SC 29203; [email protected].

Point-of-care ultrasound (POCUS) has been gaining greater traction in recent years as a way to quickly (and cost-effectively) assess for conditions including systolic dysfunction, pleural effusion, abdominal aortic aneurysms (AAAs), and deep vein thrombosis (DVT). It involves limited and specific ultrasound protocols performed at the bedside by the health care provider who is trying to answer a specific question and, thus, help guide treatment of the patient.

POCUS was first widely used by emergency physicians starting in the early 1990s with the widespread adoption of the Focused Assessment with Sonography in Trauma (FAST) scan.^1,2 Since that time, POCUS has expanded beyond trauma applications and into family medicine.

One study assessed physicians’ perceptions of POCUS after its integration into a military family medicine clinic. The study showed that physicians perceived POCUS to be relatively easy to use, not overly time consuming, and of high value to the practice.³ In fact, the literature tells us that POCUS can help decrease the cost of health care and improve outcomes,^4-7 while requiring a relatively brief training period.

If residencies are any indication, POCUS may be headed your way

Ultrasound units are becoming smaller and more affordable, and medical schools are increasingly incorporating ultrasound curricula into medical student training.⁸ As of 2016, only 6% of practicing FPs reported using non-obstetric POCUS in their practices.⁹ Similarly, a survey from 2015 reported that only 2% of family medicine residency programs had established POCUS curricula.¹⁰ However, 50% of respondents in the 2015 survey reported early-stage development or interest in developing a POCUS curriculum.

Since then a validated family medicine residency curriculum has been published,¹¹ and the American Academy of Family Physicians (AAFP) recently released a POCUS Curriculum Guideline for residencies (https://www.aafp.org/dam/AAFP/documents/medical_education_residency/program_directors/Reprint290D_POCUS.pdf).

[polldaddy:9928416]

The potential applications of POCUS in family medicine are numerous and have been reviewed in several recent publications.^12,13 In this article, we will review the evidence for the use of POCUS in 4 areas: the cardiovascular exam (FIGURES 1 and 2), the lung exam (FIGURES 3-6), the screening exam for AAAs (FIGURE 7), and the evaluation for DVT (FIGURES 8 and 9). (Obstetric and musculoskeletal applications have been sufficiently covered elsewhere.^14-17) For all of these applications, POCUS is safe, accurate, and beneficial and can be performed with a relatively small amount of training by non-radiology specialists, including FPs (TABLEs 1 and 2).

Just 2 hours of cardio POCUS training enhanced Dx accuracy

The American Society of Echocardiography (ASE) issued an expert consensus statement for focused cardiac ultrasound in 2013.¹⁸ The guideline supports non-cardiologists utilizing POCUS to assess for pericardial effusion and right and left ventricular enlargement, as well as to review global cardiac systolic function and intravascular volume status. Cardiovascular POCUS protocols are relatively easy to learn; even small amounts of training and practice can yield competency.

Point-of-care ultrasound is safe, accurate, and beneficial and can be performed with a relatively small amount of training by family physicians.

For example, a 2013 study showed that after 2 hours of training with a pocket ultrasound device, medical students and junior physicians inexperienced with POCUS were able to improve their diagnostic accuracy for heart failure from 50% to 75%.¹⁹ In another study, internal medicine residents with limited cardiac ultrasound training (ie, 20 practice exams) were able to detect decreased left ventricular ejection fraction using a handheld ultrasound device with 94% sensitivity and specificity in patients admitted to the hospital with acute decompensated heart failure.²⁰ Similarly, after only 8 hours of training, a group of Norwegian general practitioners were able to obtain measurements of systolic function with a pocket ultrasound device that were not statistically different from a cardiologist’s measurements.²¹

In another study, rural FPs attended a 4-day course and then performed focused cardiac ultrasounds on primary care patients with a clinical indication for an echocardiogram.²² The scans were uploaded to a Web-based program for remote interpretation by a cardiologist. There was high concordance between the FPs’ interpretations of the focused cardiac ultrasounds and the cardiologist’s interpretations. Only 32% of the patients in the study group required a formal follow-up echocardiogram.

Kimura et al published a POCUS protocol for the rapid assessment of patients with heart failure, called the Cardiopulmonary Limited Ultrasound Exam (CLUE).²³ The CLUE protocol utilizes 4 views to assess left ventricular systolic and diastolic function along with signs of pulmonary edema or systemic volume overload (TABLE 3²³). The presence of pulmonary edema or a plethoric inferior vena cava (IVC) was highly prognostic of in-hospital mortality. The CLUE protocol has been successfully used by novices including internal medicine residents after brief training (ie, up to 60 supervised scans) and can be performed in less than 5 minutes.^24,25

More sensitive, specific than x-rays for pulmonary diagnoses

The chest x-ray has traditionally been the imaging modality of choice to evaluate primary care pulmonary complaints. However, POCUS can be more sensitive and specific than a chest x-ray for evaluating several pulmonary diagnoses including pleural effusion, pneumonia, and pulmonary edema.

Pleural effusion can be difficult to detect with a physical exam alone. A systematic review showed that the physical exam is not sensitive for effusions <300 mL and can have even lower utility in obese patients.²⁸ While an upright lateral chest x-ray can accurately detect effusions as small as 50 mL, portable x-rays have sensitivities of only 53% to 71% for small- or moderate-sized effusions.^29,30 Ultrasound, however, has a sensitivity of 97% for small effusions.³¹

A 2016 meta-analysis showed that POCUS had a pooled sensitivity and specificity of 94% and 98%, respectively, for pleural effusions, while chest x-ray had a pooled sensitivity and specificity of 51% and 91%, respectively, when compared with computed tomography (CT) and expert sonography.³² POCUS evaluation for pleural effusion is technically simple, and at least one study showed that even novice users can achieve high diagnostic accuracy after only 3 hours of training.³³

Pneumonia is the eighth leading cause of death in the United States and the single leading cause of infectious disease death in children worldwide.^34-36 Pneumonia is a difficult diagnosis to make based on a history and physical examination alone, and the Infectious Diseases Society of America recommends diagnostic imaging to make the diagnosis.³⁷

The adult and pediatric literature clearly demonstrate that lung ultrasound is accurate at diagnosing pneumonia. In a 2015 meta-analysis of the pediatric literature, lung ultrasound had a sensitivity of 96% and a specificity of 93% and positive and negative likelihood ratios of 15.3 and 0.06, respectively.³⁸ In adults, a 2016 meta-analysis of lung ultrasound showed a pooled sensitivity and specificity of 90% and 88%, respectively, with positive and negative likelihood ratios of 6.6 and 0.08, respectively.³⁹

In 2015, a prospective study compared the accuracy of lung ultrasound and chest x-ray using CT as the gold standard.⁴⁰ Lung ultrasound had a significantly better sensitivity of 82% compared to a sensitivity of 64% for chest x-ray. Specificities were comparable at 94% for ultrasound and 90% for chest x-ray.⁴⁰

At least one study found novice sonographers to be accurate with lung POCUS for the diagnosis of pneumonia after only two 90-minute training sessions.⁴¹ Moreover, ultrasound has a more favorable safety profile, greater portability, and lower cost compared with chest x-ray and CT.

Pulmonary edema. Lung ultrasound can identify interstitial pulmonary edema via artifacts called B lines, which are produced by the reverberation of sound waves from the pleura due to the widening of the fluid-filled interlobular septa. These are distinctly different from the A-line pattern of repeating horizontal lines that is seen with normal lungs, making lung ultrasound more accurate than chest x-ray for identification of pulmonary edema.^42,43 When final diagnosis via blinded chart review is used as the reference standard, bilateral B lines on a lung ultrasound image have a sensitivity of 86% to 100% and a specificity of 92% to 98% for the diagnosis of pulmonary edema compared to chest x-ray’s sensitivity of 56.9% and specificity of 89.2%.⁴⁴ There is also a linear correlation between the number of B lines present and the extent of pulmonary edema.^42,45,46 The number of B lines decreases in real time as volume is removed in dialysis patients.⁴⁷

POCUS evaluation for B lines can be learned very quickly. Exams of novices who have performed only 5 prior exams correlate highly with those of experts who have performed more than 100 exams.⁴⁸

Simple, efficient screening method for abdominal aortic aneurysm

AAAs are present in up to 7% of men over the age of 50.⁴⁹ The mortality rate of a ruptured AAA is as high as 80% to 95%.⁵⁰ There is, however, a long prodromal period when interventions can make a significant difference, which is why accurate screening is so important.

AAA screening with ultrasound has been shown to decrease mortality.⁵¹ The current recommendation of the US Preventive Services Task Force (USPSTF) is a one-time AAA screening for all men ages 65 to 75 years who have ever smoked (Grade B).⁵² Despite the recommendations of the USPSTF, screening rates are low. One study found that only 9% of eligible patients in primary care practices received appropriate screening.⁵¹

Ultrasound performed by specialists is known to be an excellent screening test for AAA with a sensitivity of 98.9% and a specificity of 99.9%.⁵³ POCUS use by emergency medicine physicians for the evaluation of symptomatic AAA is well established in the literature. A meta-analysis including 7 studies and 655 patients showed a pooled sensitivity of 99% and a specificity of 98%.⁵⁴ Multiple studies also support primary care physicians performing POCUS AAA screening in the clinic setting.

For example, a 2012 prospective, observational study performed in Canada compared office-based ultrasound screening exams performed by a rural FP to scans performed in the hospital on the same patients.⁵⁵ The physician completed 50 training examinations. The average discrepancy in aorta diameters between the 2 was only 2 mm, which is clinically insignificant, and the office-based scans had a sensitivity and specificity of 100%.

Similarly, a second FP study performed in Barcelona, showed that an FP who performed POCUS AAA screening had 100% concordance with a radiologist.⁵⁶ Additionally, POCUS screening for AAA was not time consuming; it was performed in under 4 minutes per patient.^55,57

Ruling out DVT

DVT is a relatively rare occurrence in the ambulatory setting. However, patients who present with a painful, swollen lower extremity are much more common, and DVT must be considered and ruled out in these situations.

Although isolated distal DVTs that occur in the calf veins are usually self-limited and have a very low risk of embolization, they can progress to proximal DVTs of the thigh veins up to 20% of time.^58,59 Similarly, thrombophlebitis of the superficial lower extremity veins rarely embolizes, but can progress to a proximal DVT, especially if large segments are involved or if the segments are within 5 cm of the junction to the deep venous system.⁵⁹ The risk of missing a proximal leg DVT is high because embolization occurs up to 60% of the time if the DVT is left untreated.⁶⁰

The current standard for diagnosis of DVT is the lower extremity Doppler ultrasound examination, but obtaining same-day Doppler evaluations can be difficult in the ambulatory setting. In these instances, the American College of Chest Physicians (ACCP) recommends that even low-risk patients receive anticoagulation pending the evaluation if it cannot be obtained in the first 24 hours.⁵⁹ This approach not only increases the cost of care, but also exposes patients—many of whom will not be diagnosed with thrombosis in the end—to the risks of anticoagulation.

D-dimer blood tests have drawbacks, too. While a negative high-sensitivity D-dimer blood test in a patient with a low pre-test probability of DVT can effectively rule out a DVT, laboratory testing is not always immediately available in the ambulatory setting either.⁶¹ Additionally, false-positive rates are high, and positive D-dimer exams still require evaluation by Doppler ultrasound.

Given these limitations, performing an ultrasound at the bedside or in the exam room can allow for more timely and cost-effective care. In fact, research shows that a limited ultrasound, called the 2-region compression exam, which follows along the course of the common femoral vein and popliteal vein only, ignoring the femoral and calf veins, is highly accurate in assessing for proximal leg DVTs. As such, it has been adopted for POCUS use by emergency medicine physicians.⁶²

Multiple studies show that physicians with minimal training can perform the 2-region compression exam with a high degree of accuracy when full-leg Doppler ultrasound was used as the gold standard.^63,64 In these studies, hands-on training times ranged from only 10 minutes to 5 hours, and the exam could be performed in less than 4 minutes. A systematic review of 6 studies comparing emergency physician-performed ultrasound with radiology-performed ultrasound calculated an overall sensitivity of 0.95 (95% CI, 0.87-0.99) and specificity of 0.96 (95% CI, 0.87-0.99) for those performed by emergency physicians.⁶⁵

The main concern with the 2-region compression exam is that it can miss a distal leg DVT. As stated earlier, distal DVTs are relatively benign and tend to resolve without treatment; however, up to 20% can progress to become a dangerous proximal leg DVT.⁵⁸ Researchers have validated several methods by prospective trials to address this limitation.

Point-of-care ultrasound screening for abdominal aortic aneurysm can be performed in less than 4 minutes.

Specifically, researchers have demonstrated that patients with a low pre-test probability of DVT per the Wells scoring system could have DVT effectively ruled out with a single 2-region compression ultrasound without further evaluation.⁶⁶ In another study, researchers evaluated all patients (regardless of pretest probability) with a 2-point compression exam and found that those with negative exams could be followed with a second exam in 7 to 10 days without initiating anticoagulation. If the second one was negative, no further evaluation was needed.^67,68

And finally, researchers demonstrated that a negative 2-point compression ultrasound in combination with a concurrent negative D-dimer test was effective at ruling out DVT, regardless of pre-test probability.^69,70

A preferred approach

Given this data and the fact that in the ambulatory setting it is often easier and faster to perform a 2-region compression examination than to obtain a D-dimer laboratory test or a formal full-leg Doppler ultrasound, what follows is our preferred approach to a patient with suspected DVT in the outpatient setting (FIGURE 10).

We first assess pre-test probability using the Wells scoring system. We then perform the 2-region compression ultrasound. If the patient has low pre-test risk according to the Wells score, we rule out DVT. If the patient has moderate or high risk with a negative 2-region compression ultrasound, the patient gets a D-dimer test. If the D-dimer test is negative, we rule out DVT. If the D-dimer test is positive, we schedule the patient for a repeat 2-region compression ultrasound in 7 to 10 days. If at any time the 2-region compression evaluation is positive, we treat the patient for DVT.

CORRESPONDENCE
Paul Bornemann, MD, Palmetto Health Family Medicine Residency, Department of Family and Preventive Medicine, University of South Carolina School of Medicine, 3209 Colonial Drive, Columbia, SC 29203; [email protected].

Point-of-care ultrasound (POCUS) has been gaining greater traction in recent years as a way to quickly (and cost-effectively) assess for conditions including systolic dysfunction, pleural effusion, abdominal aortic aneurysms (AAAs), and deep vein thrombosis (DVT). It involves limited and specific ultrasound protocols performed at the bedside by the health care provider who is trying to answer a specific question and, thus, help guide treatment of the patient.

POCUS was first widely used by emergency physicians starting in the early 1990s with the widespread adoption of the Focused Assessment with Sonography in Trauma (FAST) scan.^1,2 Since that time, POCUS has expanded beyond trauma applications and into family medicine.

One study assessed physicians’ perceptions of POCUS after its integration into a military family medicine clinic. The study showed that physicians perceived POCUS to be relatively easy to use, not overly time consuming, and of high value to the practice.³ In fact, the literature tells us that POCUS can help decrease the cost of health care and improve outcomes,^4-7 while requiring a relatively brief training period.

If residencies are any indication, POCUS may be headed your way

Ultrasound units are becoming smaller and more affordable, and medical schools are increasingly incorporating ultrasound curricula into medical student training.⁸ As of 2016, only 6% of practicing FPs reported using non-obstetric POCUS in their practices.⁹ Similarly, a survey from 2015 reported that only 2% of family medicine residency programs had established POCUS curricula.¹⁰ However, 50% of respondents in the 2015 survey reported early-stage development or interest in developing a POCUS curriculum.

Since then a validated family medicine residency curriculum has been published,¹¹ and the American Academy of Family Physicians (AAFP) recently released a POCUS Curriculum Guideline for residencies (https://www.aafp.org/dam/AAFP/documents/medical_education_residency/program_directors/Reprint290D_POCUS.pdf).

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The potential applications of POCUS in family medicine are numerous and have been reviewed in several recent publications.^12,13 In this article, we will review the evidence for the use of POCUS in 4 areas: the cardiovascular exam (FIGURES 1 and 2), the lung exam (FIGURES 3-6), the screening exam for AAAs (FIGURE 7), and the evaluation for DVT (FIGURES 8 and 9). (Obstetric and musculoskeletal applications have been sufficiently covered elsewhere.^14-17) For all of these applications, POCUS is safe, accurate, and beneficial and can be performed with a relatively small amount of training by non-radiology specialists, including FPs (TABLEs 1 and 2).

Just 2 hours of cardio POCUS training enhanced Dx accuracy

The American Society of Echocardiography (ASE) issued an expert consensus statement for focused cardiac ultrasound in 2013.¹⁸ The guideline supports non-cardiologists utilizing POCUS to assess for pericardial effusion and right and left ventricular enlargement, as well as to review global cardiac systolic function and intravascular volume status. Cardiovascular POCUS protocols are relatively easy to learn; even small amounts of training and practice can yield competency.

Point-of-care ultrasound is safe, accurate, and beneficial and can be performed with a relatively small amount of training by family physicians.

For example, a 2013 study showed that after 2 hours of training with a pocket ultrasound device, medical students and junior physicians inexperienced with POCUS were able to improve their diagnostic accuracy for heart failure from 50% to 75%.¹⁹ In another study, internal medicine residents with limited cardiac ultrasound training (ie, 20 practice exams) were able to detect decreased left ventricular ejection fraction using a handheld ultrasound device with 94% sensitivity and specificity in patients admitted to the hospital with acute decompensated heart failure.²⁰ Similarly, after only 8 hours of training, a group of Norwegian general practitioners were able to obtain measurements of systolic function with a pocket ultrasound device that were not statistically different from a cardiologist’s measurements.²¹

In another study, rural FPs attended a 4-day course and then performed focused cardiac ultrasounds on primary care patients with a clinical indication for an echocardiogram.²² The scans were uploaded to a Web-based program for remote interpretation by a cardiologist. There was high concordance between the FPs’ interpretations of the focused cardiac ultrasounds and the cardiologist’s interpretations. Only 32% of the patients in the study group required a formal follow-up echocardiogram.

Kimura et al published a POCUS protocol for the rapid assessment of patients with heart failure, called the Cardiopulmonary Limited Ultrasound Exam (CLUE).²³ The CLUE protocol utilizes 4 views to assess left ventricular systolic and diastolic function along with signs of pulmonary edema or systemic volume overload (TABLE 3²³). The presence of pulmonary edema or a plethoric inferior vena cava (IVC) was highly prognostic of in-hospital mortality. The CLUE protocol has been successfully used by novices including internal medicine residents after brief training (ie, up to 60 supervised scans) and can be performed in less than 5 minutes.^24,25

More sensitive, specific than x-rays for pulmonary diagnoses

The chest x-ray has traditionally been the imaging modality of choice to evaluate primary care pulmonary complaints. However, POCUS can be more sensitive and specific than a chest x-ray for evaluating several pulmonary diagnoses including pleural effusion, pneumonia, and pulmonary edema.

Pleural effusion can be difficult to detect with a physical exam alone. A systematic review showed that the physical exam is not sensitive for effusions <300 mL and can have even lower utility in obese patients.²⁸ While an upright lateral chest x-ray can accurately detect effusions as small as 50 mL, portable x-rays have sensitivities of only 53% to 71% for small- or moderate-sized effusions.^29,30 Ultrasound, however, has a sensitivity of 97% for small effusions.³¹

A 2016 meta-analysis showed that POCUS had a pooled sensitivity and specificity of 94% and 98%, respectively, for pleural effusions, while chest x-ray had a pooled sensitivity and specificity of 51% and 91%, respectively, when compared with computed tomography (CT) and expert sonography.³² POCUS evaluation for pleural effusion is technically simple, and at least one study showed that even novice users can achieve high diagnostic accuracy after only 3 hours of training.³³

Pneumonia is the eighth leading cause of death in the United States and the single leading cause of infectious disease death in children worldwide.^34-36 Pneumonia is a difficult diagnosis to make based on a history and physical examination alone, and the Infectious Diseases Society of America recommends diagnostic imaging to make the diagnosis.³⁷

The adult and pediatric literature clearly demonstrate that lung ultrasound is accurate at diagnosing pneumonia. In a 2015 meta-analysis of the pediatric literature, lung ultrasound had a sensitivity of 96% and a specificity of 93% and positive and negative likelihood ratios of 15.3 and 0.06, respectively.³⁸ In adults, a 2016 meta-analysis of lung ultrasound showed a pooled sensitivity and specificity of 90% and 88%, respectively, with positive and negative likelihood ratios of 6.6 and 0.08, respectively.³⁹

In 2015, a prospective study compared the accuracy of lung ultrasound and chest x-ray using CT as the gold standard.⁴⁰ Lung ultrasound had a significantly better sensitivity of 82% compared to a sensitivity of 64% for chest x-ray. Specificities were comparable at 94% for ultrasound and 90% for chest x-ray.⁴⁰

At least one study found novice sonographers to be accurate with lung POCUS for the diagnosis of pneumonia after only two 90-minute training sessions.⁴¹ Moreover, ultrasound has a more favorable safety profile, greater portability, and lower cost compared with chest x-ray and CT.

Pulmonary edema. Lung ultrasound can identify interstitial pulmonary edema via artifacts called B lines, which are produced by the reverberation of sound waves from the pleura due to the widening of the fluid-filled interlobular septa. These are distinctly different from the A-line pattern of repeating horizontal lines that is seen with normal lungs, making lung ultrasound more accurate than chest x-ray for identification of pulmonary edema.^42,43 When final diagnosis via blinded chart review is used as the reference standard, bilateral B lines on a lung ultrasound image have a sensitivity of 86% to 100% and a specificity of 92% to 98% for the diagnosis of pulmonary edema compared to chest x-ray’s sensitivity of 56.9% and specificity of 89.2%.⁴⁴ There is also a linear correlation between the number of B lines present and the extent of pulmonary edema.^42,45,46 The number of B lines decreases in real time as volume is removed in dialysis patients.⁴⁷

POCUS evaluation for B lines can be learned very quickly. Exams of novices who have performed only 5 prior exams correlate highly with those of experts who have performed more than 100 exams.⁴⁸

Simple, efficient screening method for abdominal aortic aneurysm

AAAs are present in up to 7% of men over the age of 50.⁴⁹ The mortality rate of a ruptured AAA is as high as 80% to 95%.⁵⁰ There is, however, a long prodromal period when interventions can make a significant difference, which is why accurate screening is so important.

AAA screening with ultrasound has been shown to decrease mortality.⁵¹ The current recommendation of the US Preventive Services Task Force (USPSTF) is a one-time AAA screening for all men ages 65 to 75 years who have ever smoked (Grade B).⁵² Despite the recommendations of the USPSTF, screening rates are low. One study found that only 9% of eligible patients in primary care practices received appropriate screening.⁵¹

Ultrasound performed by specialists is known to be an excellent screening test for AAA with a sensitivity of 98.9% and a specificity of 99.9%.⁵³ POCUS use by emergency medicine physicians for the evaluation of symptomatic AAA is well established in the literature. A meta-analysis including 7 studies and 655 patients showed a pooled sensitivity of 99% and a specificity of 98%.⁵⁴ Multiple studies also support primary care physicians performing POCUS AAA screening in the clinic setting.

For example, a 2012 prospective, observational study performed in Canada compared office-based ultrasound screening exams performed by a rural FP to scans performed in the hospital on the same patients.⁵⁵ The physician completed 50 training examinations. The average discrepancy in aorta diameters between the 2 was only 2 mm, which is clinically insignificant, and the office-based scans had a sensitivity and specificity of 100%.

Similarly, a second FP study performed in Barcelona, showed that an FP who performed POCUS AAA screening had 100% concordance with a radiologist.⁵⁶ Additionally, POCUS screening for AAA was not time consuming; it was performed in under 4 minutes per patient.^55,57

Ruling out DVT

DVT is a relatively rare occurrence in the ambulatory setting. However, patients who present with a painful, swollen lower extremity are much more common, and DVT must be considered and ruled out in these situations.

Although isolated distal DVTs that occur in the calf veins are usually self-limited and have a very low risk of embolization, they can progress to proximal DVTs of the thigh veins up to 20% of time.^58,59 Similarly, thrombophlebitis of the superficial lower extremity veins rarely embolizes, but can progress to a proximal DVT, especially if large segments are involved or if the segments are within 5 cm of the junction to the deep venous system.⁵⁹ The risk of missing a proximal leg DVT is high because embolization occurs up to 60% of the time if the DVT is left untreated.⁶⁰

The current standard for diagnosis of DVT is the lower extremity Doppler ultrasound examination, but obtaining same-day Doppler evaluations can be difficult in the ambulatory setting. In these instances, the American College of Chest Physicians (ACCP) recommends that even low-risk patients receive anticoagulation pending the evaluation if it cannot be obtained in the first 24 hours.⁵⁹ This approach not only increases the cost of care, but also exposes patients—many of whom will not be diagnosed with thrombosis in the end—to the risks of anticoagulation.

D-dimer blood tests have drawbacks, too. While a negative high-sensitivity D-dimer blood test in a patient with a low pre-test probability of DVT can effectively rule out a DVT, laboratory testing is not always immediately available in the ambulatory setting either.⁶¹ Additionally, false-positive rates are high, and positive D-dimer exams still require evaluation by Doppler ultrasound.

Given these limitations, performing an ultrasound at the bedside or in the exam room can allow for more timely and cost-effective care. In fact, research shows that a limited ultrasound, called the 2-region compression exam, which follows along the course of the common femoral vein and popliteal vein only, ignoring the femoral and calf veins, is highly accurate in assessing for proximal leg DVTs. As such, it has been adopted for POCUS use by emergency medicine physicians.⁶²

Multiple studies show that physicians with minimal training can perform the 2-region compression exam with a high degree of accuracy when full-leg Doppler ultrasound was used as the gold standard.^63,64 In these studies, hands-on training times ranged from only 10 minutes to 5 hours, and the exam could be performed in less than 4 minutes. A systematic review of 6 studies comparing emergency physician-performed ultrasound with radiology-performed ultrasound calculated an overall sensitivity of 0.95 (95% CI, 0.87-0.99) and specificity of 0.96 (95% CI, 0.87-0.99) for those performed by emergency physicians.⁶⁵

The main concern with the 2-region compression exam is that it can miss a distal leg DVT. As stated earlier, distal DVTs are relatively benign and tend to resolve without treatment; however, up to 20% can progress to become a dangerous proximal leg DVT.⁵⁸ Researchers have validated several methods by prospective trials to address this limitation.

Point-of-care ultrasound screening for abdominal aortic aneurysm can be performed in less than 4 minutes.

Specifically, researchers have demonstrated that patients with a low pre-test probability of DVT per the Wells scoring system could have DVT effectively ruled out with a single 2-region compression ultrasound without further evaluation.⁶⁶ In another study, researchers evaluated all patients (regardless of pretest probability) with a 2-point compression exam and found that those with negative exams could be followed with a second exam in 7 to 10 days without initiating anticoagulation. If the second one was negative, no further evaluation was needed.^67,68

And finally, researchers demonstrated that a negative 2-point compression ultrasound in combination with a concurrent negative D-dimer test was effective at ruling out DVT, regardless of pre-test probability.^69,70

A preferred approach

Given this data and the fact that in the ambulatory setting it is often easier and faster to perform a 2-region compression examination than to obtain a D-dimer laboratory test or a formal full-leg Doppler ultrasound, what follows is our preferred approach to a patient with suspected DVT in the outpatient setting (FIGURE 10).

We first assess pre-test probability using the Wells scoring system. We then perform the 2-region compression ultrasound. If the patient has low pre-test risk according to the Wells score, we rule out DVT. If the patient has moderate or high risk with a negative 2-region compression ultrasound, the patient gets a D-dimer test. If the D-dimer test is negative, we rule out DVT. If the D-dimer test is positive, we schedule the patient for a repeat 2-region compression ultrasound in 7 to 10 days. If at any time the 2-region compression evaluation is positive, we treat the patient for DVT.

CORRESPONDENCE
Paul Bornemann, MD, Palmetto Health Family Medicine Residency, Department of Family and Preventive Medicine, University of South Carolina School of Medicine, 3209 Colonial Drive, Columbia, SC 29203; [email protected].

Hospital of Philadelphia

Updated results from the phase 2 ELIANA study have shown that tisagenlecleucel can produce durable complete responses (CRs) in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL).

Sixty percent of patients who received the chimeric antigen receptor (CAR) T-cell therapy achieved a CR, and 21% had a CR with incomplete hematologic recovery (CRi).

The median duration of CR/CRi was not reached at a median follow-up of 13.1 months.

The most common treatment-related adverse event (AE) was cytokine release syndrome (CRS), occurring in 77% of patients.

Researchers reported these results in NEJM. The study was sponsored by Novartis.

“This expanded, global study of CAR T-cell therapy gives us further evidence of how remarkable this treatment can be for our young patients in whom all other treatments failed,” said study author Shannon L. Maude, MD, PhD, of Children’s Hospital of Philadelphia in Pennsylvania.

“Our data show not only can we can achieve longer-term durable remissions and longer-term survival for our patients but that these personalized, cancer-fighting cells can remain in the body for months or even years, effectively doing their job.”

The trial included 75 patients who received tisagenlecleucel. At enrollment, the patients’ median age was 11 (range, 3 to 23).

Patients had received a median of 3 prior therapies (range, 1 to 8), and they had a median marrow blast percentage of 74% (range, 5 to 99).

All patients received a single infusion of tisagenlecleucel. Most (n=72) received lymphodepleting chemotherapy prior to the CAR T cells.

Results

The median duration of follow-up was 13.1 months.

The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CRi within 3 months. The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.

All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.

The researchers said tisagenlecleucel persisted in the blood for as long as 20 months.

The relapse-free survival rate among patients with a CR/CRi was 80% at 6 months and 59% at 12 months.

Seventeen patients who had achieved a CR relapsed before receiving subsequent treatment. Three patients went on to subsequent therapy before relapse but ultimately relapsed.

Relapse was also reported in 2 patients who had been classified as non-responders because they did not maintain a response for at least 28 days.

Eight patients underwent allogeneic hematopoietic stem cell transplant while in remission, and all 8 were alive when the manuscript for this study was submitted. Four patients had not relapsed, and the other 4 had unknown disease status.

At 6 months, the event-free survival rate was 73%, and the overall survival rate was 90%. At 12 months, the rates were 50% and 76%, respectively.

All patients experienced at least 1 AE, and 95% had AEs thought to be related to tisagenlecleucel. Grade 3/4 AEs occurred in 88% of patients. In 73% of patients, these AEs were thought to be related to treatment.

AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).

The median duration of CRS was 8 days (range, 1-36). Forty-seven patients were admitted to the intensive care unit to receive treatment for CRS, with a median stay of 7 days (range, 1-34).

“One of our more challenging questions—‘Can we manage the serious side effects of CAR T-cell therapy?’—was asked and answered in this global study,” said author Stephan A. Grupp, MD, PhD, of Children’s Hospital of Philadelphia.

“Some of our patients get very sick, but we showed that most toxic effects can be short-lived and reversible, with the potential for our patients to achieve durable complete remissions. That’s a pretty amazing turnaround for the high-risk child who, up until now, had little chance of surviving.”

Hospital of Philadelphia

Updated results from the phase 2 ELIANA study have shown that tisagenlecleucel can produce durable complete responses (CRs) in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL).

Sixty percent of patients who received the chimeric antigen receptor (CAR) T-cell therapy achieved a CR, and 21% had a CR with incomplete hematologic recovery (CRi).

The median duration of CR/CRi was not reached at a median follow-up of 13.1 months.

The most common treatment-related adverse event (AE) was cytokine release syndrome (CRS), occurring in 77% of patients.

Researchers reported these results in NEJM. The study was sponsored by Novartis.

“This expanded, global study of CAR T-cell therapy gives us further evidence of how remarkable this treatment can be for our young patients in whom all other treatments failed,” said study author Shannon L. Maude, MD, PhD, of Children’s Hospital of Philadelphia in Pennsylvania.

“Our data show not only can we can achieve longer-term durable remissions and longer-term survival for our patients but that these personalized, cancer-fighting cells can remain in the body for months or even years, effectively doing their job.”

The trial included 75 patients who received tisagenlecleucel. At enrollment, the patients’ median age was 11 (range, 3 to 23).

Patients had received a median of 3 prior therapies (range, 1 to 8), and they had a median marrow blast percentage of 74% (range, 5 to 99).

All patients received a single infusion of tisagenlecleucel. Most (n=72) received lymphodepleting chemotherapy prior to the CAR T cells.

Results

The median duration of follow-up was 13.1 months.

The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CRi within 3 months. The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.

All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.

The researchers said tisagenlecleucel persisted in the blood for as long as 20 months.

The relapse-free survival rate among patients with a CR/CRi was 80% at 6 months and 59% at 12 months.

Seventeen patients who had achieved a CR relapsed before receiving subsequent treatment. Three patients went on to subsequent therapy before relapse but ultimately relapsed.

Relapse was also reported in 2 patients who had been classified as non-responders because they did not maintain a response for at least 28 days.

Eight patients underwent allogeneic hematopoietic stem cell transplant while in remission, and all 8 were alive when the manuscript for this study was submitted. Four patients had not relapsed, and the other 4 had unknown disease status.

At 6 months, the event-free survival rate was 73%, and the overall survival rate was 90%. At 12 months, the rates were 50% and 76%, respectively.

All patients experienced at least 1 AE, and 95% had AEs thought to be related to tisagenlecleucel. Grade 3/4 AEs occurred in 88% of patients. In 73% of patients, these AEs were thought to be related to treatment.

AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).

The median duration of CRS was 8 days (range, 1-36). Forty-seven patients were admitted to the intensive care unit to receive treatment for CRS, with a median stay of 7 days (range, 1-34).

“One of our more challenging questions—‘Can we manage the serious side effects of CAR T-cell therapy?’—was asked and answered in this global study,” said author Stephan A. Grupp, MD, PhD, of Children’s Hospital of Philadelphia.

“Some of our patients get very sick, but we showed that most toxic effects can be short-lived and reversible, with the potential for our patients to achieve durable complete remissions. That’s a pretty amazing turnaround for the high-risk child who, up until now, had little chance of surviving.”

Hospital of Philadelphia

Updated results from the phase 2 ELIANA study have shown that tisagenlecleucel can produce durable complete responses (CRs) in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL).

Sixty percent of patients who received the chimeric antigen receptor (CAR) T-cell therapy achieved a CR, and 21% had a CR with incomplete hematologic recovery (CRi).

The median duration of CR/CRi was not reached at a median follow-up of 13.1 months.

The most common treatment-related adverse event (AE) was cytokine release syndrome (CRS), occurring in 77% of patients.

Researchers reported these results in NEJM. The study was sponsored by Novartis.

“This expanded, global study of CAR T-cell therapy gives us further evidence of how remarkable this treatment can be for our young patients in whom all other treatments failed,” said study author Shannon L. Maude, MD, PhD, of Children’s Hospital of Philadelphia in Pennsylvania.

“Our data show not only can we can achieve longer-term durable remissions and longer-term survival for our patients but that these personalized, cancer-fighting cells can remain in the body for months or even years, effectively doing their job.”

The trial included 75 patients who received tisagenlecleucel. At enrollment, the patients’ median age was 11 (range, 3 to 23).

Patients had received a median of 3 prior therapies (range, 1 to 8), and they had a median marrow blast percentage of 74% (range, 5 to 99).

All patients received a single infusion of tisagenlecleucel. Most (n=72) received lymphodepleting chemotherapy prior to the CAR T cells.

Results

The median duration of follow-up was 13.1 months.

The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CRi within 3 months. The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.

All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.

The researchers said tisagenlecleucel persisted in the blood for as long as 20 months.

The relapse-free survival rate among patients with a CR/CRi was 80% at 6 months and 59% at 12 months.

Seventeen patients who had achieved a CR relapsed before receiving subsequent treatment. Three patients went on to subsequent therapy before relapse but ultimately relapsed.

Relapse was also reported in 2 patients who had been classified as non-responders because they did not maintain a response for at least 28 days.

Eight patients underwent allogeneic hematopoietic stem cell transplant while in remission, and all 8 were alive when the manuscript for this study was submitted. Four patients had not relapsed, and the other 4 had unknown disease status.

At 6 months, the event-free survival rate was 73%, and the overall survival rate was 90%. At 12 months, the rates were 50% and 76%, respectively.

All patients experienced at least 1 AE, and 95% had AEs thought to be related to tisagenlecleucel. Grade 3/4 AEs occurred in 88% of patients. In 73% of patients, these AEs were thought to be related to treatment.

AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).

The median duration of CRS was 8 days (range, 1-36). Forty-seven patients were admitted to the intensive care unit to receive treatment for CRS, with a median stay of 7 days (range, 1-34).

“One of our more challenging questions—‘Can we manage the serious side effects of CAR T-cell therapy?’—was asked and answered in this global study,” said author Stephan A. Grupp, MD, PhD, of Children’s Hospital of Philadelphia.

“Some of our patients get very sick, but we showed that most toxic effects can be short-lived and reversible, with the potential for our patients to achieve durable complete remissions. That’s a pretty amazing turnaround for the high-risk child who, up until now, had little chance of surviving.”

Image from NIAID

The US Food and Drug Administration (FDA) has placed BPX-501, a T-cell therapy being evaluated in patients who undergo haploidentical hematopoietic stem cell transplants (HSCTs), on clinical hold.

Three cases of encephalopathy possibly related to BPX-501 prompted the agency to impose the hold.

Bellicum Pharmaceuticals is the developer of BPX-501, and the company was conducting 4 trials in the US in children and adults with hematologic disorders.

The BPX-501 registration trial in Europe is not affected by the clinical hold.

BPX-501 is designed to fight infection, support engraftment, prevent disease relapse, and potentially stop graft-versus-host disease (GVHD) should it occur.

BPX-501 contains a safety switch, CaspaCIDe®, that can be activated with the administration of rimiducid to kill the toxic T cells in the event of GVHD.

The 3 cases of encephalopathy are complex, according to a company press release, and have confounding factors. These include prior failed transplants, prior history of immunodeficiency, concurrent infection, and administration of rimiducid in combination with other medications.

Encephalopathy had not emerged as an adverse event in 240 patients treated with the cell therapy, until now.

BPX-501 had produced encouraging results, according to trial data presented at EHA 2017 and ASH 2017 (abstract 211*).

In this trial, 112 pediatric patients were transfused with BPX-501 cells about 2 weeks after transplant. Patients had acute leukemia (n=53), primary immune deficiencies (n=26), erythroid disorders (n=17), Fanconi anemia (n=7), and other diseases (n=9).

Investigators reported that infused cells expanded and persisted, with peak expansion reached at 9 months after infusion. Investigators continued to detect BPX-501 cells after 2 years.

The European Commission granted BPX-501 orphan drug designation for the agent for treatment in HSCT, and for the activator agent rimiducid for the treatment of GVHD.

And the FDA had granted the agents orphan drug status as a combination replacement T-cell therapy for the treatment of immunodeficiency and GVHD after HSCT.

Bellicum says it is working with the FDA to evaluate the risk of encephalopathy in patients receiving BPX-501.

* Data in the abstract were updated in the oral presentation and reported on the company’s website.

Image from NIAID

The US Food and Drug Administration (FDA) has placed BPX-501, a T-cell therapy being evaluated in patients who undergo haploidentical hematopoietic stem cell transplants (HSCTs), on clinical hold.

Three cases of encephalopathy possibly related to BPX-501 prompted the agency to impose the hold.

Bellicum Pharmaceuticals is the developer of BPX-501, and the company was conducting 4 trials in the US in children and adults with hematologic disorders.

The BPX-501 registration trial in Europe is not affected by the clinical hold.

BPX-501 is designed to fight infection, support engraftment, prevent disease relapse, and potentially stop graft-versus-host disease (GVHD) should it occur.

BPX-501 contains a safety switch, CaspaCIDe®, that can be activated with the administration of rimiducid to kill the toxic T cells in the event of GVHD.

The 3 cases of encephalopathy are complex, according to a company press release, and have confounding factors. These include prior failed transplants, prior history of immunodeficiency, concurrent infection, and administration of rimiducid in combination with other medications.

Encephalopathy had not emerged as an adverse event in 240 patients treated with the cell therapy, until now.

BPX-501 had produced encouraging results, according to trial data presented at EHA 2017 and ASH 2017 (abstract 211*).

In this trial, 112 pediatric patients were transfused with BPX-501 cells about 2 weeks after transplant. Patients had acute leukemia (n=53), primary immune deficiencies (n=26), erythroid disorders (n=17), Fanconi anemia (n=7), and other diseases (n=9).

Investigators reported that infused cells expanded and persisted, with peak expansion reached at 9 months after infusion. Investigators continued to detect BPX-501 cells after 2 years.

The European Commission granted BPX-501 orphan drug designation for the agent for treatment in HSCT, and for the activator agent rimiducid for the treatment of GVHD.

And the FDA had granted the agents orphan drug status as a combination replacement T-cell therapy for the treatment of immunodeficiency and GVHD after HSCT.

Bellicum says it is working with the FDA to evaluate the risk of encephalopathy in patients receiving BPX-501.

* Data in the abstract were updated in the oral presentation and reported on the company’s website.

Image from NIAID

The US Food and Drug Administration (FDA) has placed BPX-501, a T-cell therapy being evaluated in patients who undergo haploidentical hematopoietic stem cell transplants (HSCTs), on clinical hold.

Three cases of encephalopathy possibly related to BPX-501 prompted the agency to impose the hold.

Bellicum Pharmaceuticals is the developer of BPX-501, and the company was conducting 4 trials in the US in children and adults with hematologic disorders.

The BPX-501 registration trial in Europe is not affected by the clinical hold.

BPX-501 is designed to fight infection, support engraftment, prevent disease relapse, and potentially stop graft-versus-host disease (GVHD) should it occur.

BPX-501 contains a safety switch, CaspaCIDe®, that can be activated with the administration of rimiducid to kill the toxic T cells in the event of GVHD.

The 3 cases of encephalopathy are complex, according to a company press release, and have confounding factors. These include prior failed transplants, prior history of immunodeficiency, concurrent infection, and administration of rimiducid in combination with other medications.

Encephalopathy had not emerged as an adverse event in 240 patients treated with the cell therapy, until now.

BPX-501 had produced encouraging results, according to trial data presented at EHA 2017 and ASH 2017 (abstract 211*).

In this trial, 112 pediatric patients were transfused with BPX-501 cells about 2 weeks after transplant. Patients had acute leukemia (n=53), primary immune deficiencies (n=26), erythroid disorders (n=17), Fanconi anemia (n=7), and other diseases (n=9).

Investigators reported that infused cells expanded and persisted, with peak expansion reached at 9 months after infusion. Investigators continued to detect BPX-501 cells after 2 years.

The European Commission granted BPX-501 orphan drug designation for the agent for treatment in HSCT, and for the activator agent rimiducid for the treatment of GVHD.

And the FDA had granted the agents orphan drug status as a combination replacement T-cell therapy for the treatment of immunodeficiency and GVHD after HSCT.

Bellicum says it is working with the FDA to evaluate the risk of encephalopathy in patients receiving BPX-501.

* Data in the abstract were updated in the oral presentation and reported on the company’s website.